**Meet the editor**

Dr Shailendra K. Saxena is a Medical Microbiologist at CSIR-Centre for Cellular and Molecular Biology (CCMB) in India. The main research interests of his group are to understand the epidemiology and molecular mechanisms of host-defense during human viral infections and to develop new predictive, preventive and therapeutic strategies for them using JEV and HIV as a model. His

research work has been published in various high impact factor journals with high citation. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award and named as "Global Leader in Science" by The Scientist magazine (USA).

Contents

**Preface IX**

**Infection 3**

**Patients 57** Nitya Nathwani

**Section 2 HIV Screening 75**

**Section 1 HIV and Altered Immune Responses 1**

Chapter 1 **Immune Responses and Cell Signaling During Chronic HIV**

Chapter 2 **Role of Dendritic Cell Subsets on HIV-Specific Immunity 31** Wilfried Posch, Cornelia Lass-Flörl and Doris Wilflingseder

Chapter 3 **Hematopoietic Stem Cell Transplantation in HIV Infected**

Chapter 4 **Screening for HIV Infection in Pregnancy 77**

Teddy Charles Adias and Osaro Erhabor

**Limiting Settings 95**

**Section 3 HIV and NeuroAIDS 107**

**Social Issues 109**

Abdulkarim Alhetheel, Mahmoud Aly and Marko Kryworuchko

Chi Dola, Maga Martinez, Olivia Chang and Amanda Johnson

Chapter 5 **Human Immunodeficiency Virus Testing Algorithm in Resource**

Chapter 6 **NeuroAIDS: Mechanisms, Causes, Prevalence, Diagnostics and**

Shailendra K. Saxena, Sneham Tiwari and Madhavan P.N. Nair

### Contents

### **Preface XIII**


Shailendra K. Saxena, Sneham Tiwari and Madhavan P.N. Nair


Chapter 17 **Prevention of Sexually Transmitted HIV Infection 385**

Chapter 18 **HIV-2 Interaction with Target Cell Receptors, or Why HIV-2 is**

Chapter 19 **Interaction of FIV with Heterologous Microbes in the Feline**

Joseph Ongrádi, Stercz Balázs, Kövesdi Valéria, Nagy Károly and

Contents **VII**

Jose G. Castro and Maria L. Alcaide

**Less Pathogenic than HIV-1 411** José Miguel Azevedo-Pereira

**Section 6 Recent Advances 409**

**AIDS Model 447**

Pistello Mauro

Chapter 17 **Prevention of Sexually Transmitted HIV Infection 385** Jose G. Castro and Maria L. Alcaide

### **Section 6 Recent Advances 409**

Chapter 7 **Human Immunodeficiency Virus Infection and Co-Morbid**

Chapter 8 **Neurological Manifestations of HIV-1 Infection and Markers**

Chapter 9 **Persistence of HIV-Associated Neurocognitive Disorders in the**

G.A. Agbelusi, O.M. Eweka, K.A. Ùmeizudike and M. Okoh

Jennifer M. King, Brigid K. Jensen, Patrick J. Gannon and Cagla Akay

Paula Freitas, Davide Carvalho, Selma Souto, António Sarmento and

Rehana Basri and Wan Mohamad Wan Majdiah

**Mental Distress 125**

**VI** Contents

**for HIV Progression 137**

**Section 4 Manifestations of HIV Infection 207**

Chapter 10 **Oral Manifestations of HIV 209**

José Luís Medina

Chapter 13 **HIV/AIDS: Vertical Transmission 301** Enrique Valdés Rubio

**Sub Saharan Africa 325**

**Restoration Disease 351**

and Robert Muga

O. Erhabor, T.C. Adias and C.I. Akani

**Section 5 Prevention and Treatment of HIV Infection 349**

Chapter 15 **The Downside of an Effective cART: The Immune**

Claudia Colomba and Raffaella Rubino

Chapter 16 **HIV Infection and Viral Hepatitis in Drug Abusers 367**

Arantza Sanvisens, Ferran Bolao, Gabriel Vallecillo, Marta Torrens, Daniel Fuster, Santiago Pérez-Hoyos, Jordi Tor, Inmaculada Rivas

Peter J. Chipimo and Knut Fylkesnes

**Era of Antiretroviral Therapy 161**

Chapter 11 **Endocrine Manifestations of HIV Infection 243** Bakari Adamu Girei and Sani-Bello Fatima

**Insulin-Resistance Syndrome 261**

Chapter 12 **Lipodystrophy: The Metabolic Link of HIV Infection with**

Chapter 14 **Reproductive Health Challenges of Living with HIV-Infection in**


Preface

poorly understood.

signed drugs.

a role in their exponential proliferation.

During the past three decades, the world scientific community has witnessed major achieve‐ ments understanding the pathogenesis of Human immunodeficiency virus (HIV) which leads to a deadly catastrophic disease acquired immune deficiency syndrome (AIDS). As per recent UNAIDS reports currently ~34 million adults and children are estimated to be living with HIV. Ever since the discovery of HIV, it has been an ultimate challenge to the health and scientific authorities. There is a constant research being done by scientists worldwide to find ways to combat with HIV. HIV has occupied place as a topmost health and social disas‐ ter. It is affecting several developing economies. Thus it becomes an urgency to find ways of management against HIV infection. To device a way, basic and thorough knowledge about HIV, stands as a priority. We need to understand viral morphology, functions, and mecha‐ nisms of viral replication, budding, cell signaling, pathogenesis, interaction with host fac‐ tors, and various other important aspects. However many aspects of HIV infection are still

HIV-1, a retrovirus, attacks the T-lymphocytes of the hosts, and causes several multifaceted altered immune responses and finally leads to fatality. HIV-1 displays extraordinary genetic variation, leading to the classification of the viral strains into phylogenetically distinct groups and subtypes. Amongst the various subtype/clade (A to K) of HIV-1, subtype C is linked to ~48% of the infections globally and is associated with rapidly growing epidemics in Sub-Saharan Africa and parts of Asia, including India and China. In addition to genetic and demographic factors, biological properties unique to the subtype of HIV may also play

HIV is capable of being latent and hidden in various reservoirs in the body where drug tar‐ geting becomes impossible. HIV can enter brain and attack neuronal cells and deregulate there functioning which leads to neuropathogenesis. Hence drug targeting to viral reser‐ voirs like brain stands as a big issue. Drugs capable of travelling across the Blood Brain Bar‐ rier (BBB) are an urgent need. Along with these genes specific targeting drugs are also important. These drugs can focus on one particular gene or a part of gene that is motif, which is conserved and is most stable. This stable part can be very well targeted by the de‐

Henceforth, keeping in mind all the issues, this book gives a comprehensive overview of HIV and AIDS including NeuroAIDS. The book is divided into several parts which cover various topics deeply, explaining HIV and related pathology, immunity and immunopathol‐ ogy, altered immune responses, screening, diagnosis, manifestations, prevention, treatment, epidemiology and etiology to current clinical recommendations in management of HIV/

### Preface

During the past three decades, the world scientific community has witnessed major achieve‐ ments understanding the pathogenesis of Human immunodeficiency virus (HIV) which leads to a deadly catastrophic disease acquired immune deficiency syndrome (AIDS). As per recent UNAIDS reports currently ~34 million adults and children are estimated to be living with HIV. Ever since the discovery of HIV, it has been an ultimate challenge to the health and scientific authorities. There is a constant research being done by scientists worldwide to find ways to combat with HIV. HIV has occupied place as a topmost health and social disas‐ ter. It is affecting several developing economies. Thus it becomes an urgency to find ways of management against HIV infection. To device a way, basic and thorough knowledge about HIV, stands as a priority. We need to understand viral morphology, functions, and mecha‐ nisms of viral replication, budding, cell signaling, pathogenesis, interaction with host fac‐ tors, and various other important aspects. However many aspects of HIV infection are still poorly understood.

HIV-1, a retrovirus, attacks the T-lymphocytes of the hosts, and causes several multifaceted altered immune responses and finally leads to fatality. HIV-1 displays extraordinary genetic variation, leading to the classification of the viral strains into phylogenetically distinct groups and subtypes. Amongst the various subtype/clade (A to K) of HIV-1, subtype C is linked to ~48% of the infections globally and is associated with rapidly growing epidemics in Sub-Saharan Africa and parts of Asia, including India and China. In addition to genetic and demographic factors, biological properties unique to the subtype of HIV may also play a role in their exponential proliferation.

HIV is capable of being latent and hidden in various reservoirs in the body where drug tar‐ geting becomes impossible. HIV can enter brain and attack neuronal cells and deregulate there functioning which leads to neuropathogenesis. Hence drug targeting to viral reser‐ voirs like brain stands as a big issue. Drugs capable of travelling across the Blood Brain Bar‐ rier (BBB) are an urgent need. Along with these genes specific targeting drugs are also important. These drugs can focus on one particular gene or a part of gene that is motif, which is conserved and is most stable. This stable part can be very well targeted by the de‐ signed drugs.

Henceforth, keeping in mind all the issues, this book gives a comprehensive overview of HIV and AIDS including NeuroAIDS. The book is divided into several parts which cover various topics deeply, explaining HIV and related pathology, immunity and immunopathol‐ ogy, altered immune responses, screening, diagnosis, manifestations, prevention, treatment, epidemiology and etiology to current clinical recommendations in management of HIV/ AIDS including NeuroAIDS, It also highlights the ongoing issues, recent advances and fu‐ ture directions in diagnostic approaches and therapeutic strategies.

The authors and editors of the book hope that this work might increase the interest in this field of research and that the readers will find it useful for their investigations, management and clinical usage. Also I would like to thank Council of Scientific and Industrial Research (CSIR-CCMB), Director CCMB Dr CM Rao, colleagues, family, and parents who gave me a lot of encouragement and support during the work on this book.

#### **Shailendra K. Saxena, PhD, DCAP, FAEB,**

**Section 1**

**HIV and Altered Immune Responses**

CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India **HIV and Altered Immune Responses**

AIDS including NeuroAIDS, It also highlights the ongoing issues, recent advances and fu‐

The authors and editors of the book hope that this work might increase the interest in this field of research and that the readers will find it useful for their investigations, management and clinical usage. Also I would like to thank Council of Scientific and Industrial Research (CSIR-CCMB), Director CCMB Dr CM Rao, colleagues, family, and parents who gave me a

> **Shailendra K. Saxena, PhD, DCAP, FAEB,** CSIR-Centre for Cellular and Molecular Biology,

> > Hyderabad, India

ture directions in diagnostic approaches and therapeutic strategies.

X Preface

lot of encouragement and support during the work on this book.

**Chapter 1**

**Immune Responses and**

Marko Kryworuchko

**1. Introduction**

pathogen such as HIV.

http://dx.doi.org/10.5772/53010

Abdulkarim Alhetheel, Mahmoud Aly and

Additional information is available at the end of the chapter

**2. Human immunodeficiency virus (HIV)**

**Cell Signaling During Chronic HIV Infection**

The immune response can be defined by the reaction of the immune system to a particular antigen to which it is exposed. In order to understand immune responses against an infectious agent such as human immunodeficiency virus (HIV) and their regulation during the course of chronic HIV infection, we will provide a brief overview of HIV and its proteins and attempt to shed light on this disease process. We will also review the immune system, its components and describe how these components interact at the molecular levels to fight an invading

AIDS (Acquired Immuno-Deficiency Syndrome) in patients was discovered in 1981 and characterized by the appearance symptoms including persistent lymphadenopathy and opportunistic infections such as Kaposi sarcoma, *Pneumocystis carinii* pneumonia. In addition, it was found that all of these patients shared a common defect in cell-mediated immunity characterized by a significant decrease in CD4+T lymphocytes, later revealed to be a principal target of infection [1-3]. Three years later, the causative agent of AIDS was identified as HIV [4, 5]. HIV was classified under the *lentivirus* genus and the *Retroviridae* family. It is an enveloped virus with a size of about 100 nm in diameter. Its genome consists of two identical copies of positive-sense single stranded RNA (ssRNA) that are reverse transcribed into cDNA in infected cells [2, 5]. Each ssRNA is about 9,500 nucleotides in length, and encodes three structural genes called gag, pol, env, and a complex of several other nonstructural regulatory

and reproduction in any medium, provided the original work is properly cited.

© 2013 Alhetheel et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

### **Chapter 1**

### **Immune Responses and Cell Signaling During Chronic HIV Infection**

Abdulkarim Alhetheel, Mahmoud Aly and Marko Kryworuchko

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53010

### **1. Introduction**

The immune response can be defined by the reaction of the immune system to a particular antigen to which it is exposed. In order to understand immune responses against an infectious agent such as human immunodeficiency virus (HIV) and their regulation during the course of chronic HIV infection, we will provide a brief overview of HIV and its proteins and attempt to shed light on this disease process. We will also review the immune system, its components and describe how these components interact at the molecular levels to fight an invading pathogen such as HIV.

### **2. Human immunodeficiency virus (HIV)**

AIDS (Acquired Immuno-Deficiency Syndrome) in patients was discovered in 1981 and characterized by the appearance symptoms including persistent lymphadenopathy and opportunistic infections such as Kaposi sarcoma, *Pneumocystis carinii* pneumonia. In addition, it was found that all of these patients shared a common defect in cell-mediated immunity characterized by a significant decrease in CD4+T lymphocytes, later revealed to be a principal target of infection [1-3]. Three years later, the causative agent of AIDS was identified as HIV [4, 5]. HIV was classified under the *lentivirus* genus and the *Retroviridae* family. It is an enveloped virus with a size of about 100 nm in diameter. Its genome consists of two identical copies of positive-sense single stranded RNA (ssRNA) that are reverse transcribed into cDNA in infected cells [2, 5]. Each ssRNA is about 9,500 nucleotides in length, and encodes three structural genes called gag, pol, env, and a complex of several other nonstructural regulatory

© 2013 Alhetheel et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

genes known as tat, rev, nef, vif, vpr, and vpu [2, 5]. The gag gene encodes the viral structural proteins including p24 (capsid), p17 (matrix), p7 (nucleocapsid). The pol gene, on the other hand, encodes viral enzymes including p32 (integrase), p66 and p51 (reverse transcriptase), and p10 (protease). The env gene encodes the coat glycoproteins gp120 (surface) and gp41 (transmembrane), which play a major role in viral attachment and fusion with host target cell membranes. The nonstructural genes including transactivator of transcription (Tat), regulator of virion protein expression (Rev), negative regulatory factor (Nef), viral infectivity factor (Vif), viral protein R (Vpr), and viral protein U (Vpu) proteins, respectively, are also essential for viral replication and pathogenesis [2, 5].

Monocytes, which are the precursors of macrophages, as a part of the innate immune system, play a major role in controlling and clearing pathogens. They exhibit antimicrobial, antifungal, and antiparasitic properties [4,6-8]. They possess phagocytic and endocytic activity. In addition, they act as antigen presenting cells by uptaking, processing, and presenting antigen in the context of major histocompatibility complex (MHC) class II to CD4+ T cells. Moreover, they secrete inflammatory cytokines such as IFN type-I (IFN-α/β), interleukin (IL)-1, IL-6, IL-12, and chemokines such as IL-8 [4,6-8]. This stimulates the adaptive immune system and leads to the activation and differentiation of B and T lymphocyte populations. These important monocyte/macrophage (M/M) functions are largely driven and regulated by the responsive‐ ness of these cells to numerous cytokines such as IFN-γ, IL-10, and Tumor Necrosis Factor (TNF)-α, and signals delivered to them via the TLR family through recognition of different microbial products such as bacterial lipopolysaccharide (LPS) and viral proteins and nucleic

Immune Responses and Cell Signaling During Chronic HIV Infection

http://dx.doi.org/10.5772/53010

5

B and T lymphocytes form the arm of the adaptive and antigen-specific immune response. B lymphocytes are antigen presenting cells, upon antigenic and cytokine stimulation they differentiate into plasma cells which produce antigen-specific antibodies. While T lympho‐ cytes are divided into two distinct populations: helper and cytotoxic cells which are differ in their function T helper lymphocytes express the CD4 surface receptor, recognize antigens presented as peptide epitopes bound to MHC class II molecules expressed on the surface of antigen presenting cells, and function mainly as cytokine producing cells to 'help' the devel‐ opment of the immune response. Activated CD4+ T cells differentiate into T helper (Th)-1 and Th-2 effectors, and memory cell sub-populations. The Th-1 and Th-2 subsets of CD4+ T cells were originally defined by their polarized cytokine production patterns [15,16]. Th-1 cells produce IFN-γ, IL-2, IL-12 and lymphotoxin-α, which enhance antigen presentation, phago‐ cytosis, and cell-mediated cytotoxicity. On the other hand, Th-2 cells secrete IL-4, IL-5, IL-9, IL-10, and IL-13, promoting more of an antibody response [16-18]. Cytotoxic T lymphocytes however, express the CD8 surface receptor, and recognize antigenic peptide epitopes present‐ ed on cell surface MHC class I molecules. Antigen-activated CD8+ T cells also proliferate and differentiate into effectors and memory cell populations, largely in response to cytokines that share the common γc receptor, such as IL-2, IL-15, and IL-7. Cytotoxic T cells secrete IFN-γ, which inhibits virus replication, as well as perforin, and granzymes in order to kill virus-

HIV is commonly transmitted by sexual contact, and thus it initially interacts with and activates the innate immune system and antigen presenting cells including macrophages and dendritic cells at the mucosal surfaces [5,19,20]. Importantly, these cells then migrate to the lymphoid tissues and thereby also deliver the virus to other susceptible cells located at these sites. In the lymphoid tissues, HIV interacts and infects other cells such as CD4+ T cells and is able to disseminate to other areas such as the brain and gut [5,21]. Subsequently, inflammatory cells

acids including those of HIV [4,6-8].

**3.2. The adaptive immune system**

infected cells.

**3.3. HIV and the cellular immune response**

### **3. The immune system and its cellular components**

The immune system is a very complex and dynamic network, which can be broadly divided into innate and adaptive components [4,6,7]. The cellular components of innate immunity include dendritic cells, natural killer (NK) cells, NK T cells, macrophages, and granulocytes, whereas, the adaptive immunity is mediated by B and T lymphocytes [4,6-8]. The components of both branches act in conjunction and are regulated by soluble mediator proteins known as cytokines and chemokines in order to fight, clear, and protect the host from a wide variety of pathogens [4,6-8].

#### **3.1. The innate immune system**

The innate immune system is the first line of defense against invading pathogens. Viral infections including HIV induce the interferon (IFN) response that is characterized by the production and secretion of pro-inflammatory cytokines including type-I IFN (IFN-α/β). These cytokines have antimicrobial and anti-proliferative properties and serve to propagate the adaptive immune responses [9]. In humans, cellular RNA molecules are short stem secondary structures. In contrast, RNA viruses produce long dsRNA molecules in the infected cells as a part of their life cycle. Thus, the long dsRNA can be recognized as a foreign molecule and triggers both cellular and humoral innate immune responses [10]. There are two well charac‐ terized ways in which a cell can recognize pathogens. Distinct extracellular pathogen compo‐ nents are recognized by different Toll- like receptors (TLR) expressed on the cell surface or in the endosome such as TLR2, TLR3, TLR4, TLR7, TLR8, and TLR9 [11]. Intracellular replicating pathogens however, are recognized by RNA helicases, which are encoded by the retinoic acidinducible gene I (RIG-I) and/or melanoma differentiation-associated gene 5 (MDA5) [12]. Following viral recognition, the activation and translocation of the transcription factor nuclear factor κB (NFκB) and interferon-regulatory factor (IRF)-3 to the nucleus occurs and promotes the transcription of IFN type I [13]. Production of type-I IFN stimulates the surrounding cells to produce a wide range of antiviral proteins including protein kinase R (PKR), myxovirus resistance factor, 2'-5' oligoadenylate synthase/RNaseL and dsRNA adenosine deaminase 1, which subsequently leads to the activation of eukaryotic initiation factor (eIF)-2, and transla‐ tion inhibition of both host and viral mRNAs [14].

Monocytes, which are the precursors of macrophages, as a part of the innate immune system, play a major role in controlling and clearing pathogens. They exhibit antimicrobial, antifungal, and antiparasitic properties [4,6-8]. They possess phagocytic and endocytic activity. In addition, they act as antigen presenting cells by uptaking, processing, and presenting antigen in the context of major histocompatibility complex (MHC) class II to CD4+ T cells. Moreover, they secrete inflammatory cytokines such as IFN type-I (IFN-α/β), interleukin (IL)-1, IL-6, IL-12, and chemokines such as IL-8 [4,6-8]. This stimulates the adaptive immune system and leads to the activation and differentiation of B and T lymphocyte populations. These important monocyte/macrophage (M/M) functions are largely driven and regulated by the responsive‐ ness of these cells to numerous cytokines such as IFN-γ, IL-10, and Tumor Necrosis Factor (TNF)-α, and signals delivered to them via the TLR family through recognition of different microbial products such as bacterial lipopolysaccharide (LPS) and viral proteins and nucleic acids including those of HIV [4,6-8].

#### **3.2. The adaptive immune system**

genes known as tat, rev, nef, vif, vpr, and vpu [2, 5]. The gag gene encodes the viral structural proteins including p24 (capsid), p17 (matrix), p7 (nucleocapsid). The pol gene, on the other hand, encodes viral enzymes including p32 (integrase), p66 and p51 (reverse transcriptase), and p10 (protease). The env gene encodes the coat glycoproteins gp120 (surface) and gp41 (transmembrane), which play a major role in viral attachment and fusion with host target cell membranes. The nonstructural genes including transactivator of transcription (Tat), regulator of virion protein expression (Rev), negative regulatory factor (Nef), viral infectivity factor (Vif), viral protein R (Vpr), and viral protein U (Vpu) proteins, respectively, are also essential for

The immune system is a very complex and dynamic network, which can be broadly divided into innate and adaptive components [4,6,7]. The cellular components of innate immunity include dendritic cells, natural killer (NK) cells, NK T cells, macrophages, and granulocytes, whereas, the adaptive immunity is mediated by B and T lymphocytes [4,6-8]. The components of both branches act in conjunction and are regulated by soluble mediator proteins known as cytokines and chemokines in order to fight, clear, and protect the host from a wide variety of

The innate immune system is the first line of defense against invading pathogens. Viral infections including HIV induce the interferon (IFN) response that is characterized by the production and secretion of pro-inflammatory cytokines including type-I IFN (IFN-α/β). These cytokines have antimicrobial and anti-proliferative properties and serve to propagate the adaptive immune responses [9]. In humans, cellular RNA molecules are short stem secondary structures. In contrast, RNA viruses produce long dsRNA molecules in the infected cells as a part of their life cycle. Thus, the long dsRNA can be recognized as a foreign molecule and triggers both cellular and humoral innate immune responses [10]. There are two well charac‐ terized ways in which a cell can recognize pathogens. Distinct extracellular pathogen compo‐ nents are recognized by different Toll- like receptors (TLR) expressed on the cell surface or in the endosome such as TLR2, TLR3, TLR4, TLR7, TLR8, and TLR9 [11]. Intracellular replicating pathogens however, are recognized by RNA helicases, which are encoded by the retinoic acidinducible gene I (RIG-I) and/or melanoma differentiation-associated gene 5 (MDA5) [12]. Following viral recognition, the activation and translocation of the transcription factor nuclear factor κB (NFκB) and interferon-regulatory factor (IRF)-3 to the nucleus occurs and promotes the transcription of IFN type I [13]. Production of type-I IFN stimulates the surrounding cells to produce a wide range of antiviral proteins including protein kinase R (PKR), myxovirus resistance factor, 2'-5' oligoadenylate synthase/RNaseL and dsRNA adenosine deaminase 1, which subsequently leads to the activation of eukaryotic initiation factor (eIF)-2, and transla‐

viral replication and pathogenesis [2, 5].

4 Current Perspectives in HIV Infection

pathogens [4,6-8].

**3.1. The innate immune system**

tion inhibition of both host and viral mRNAs [14].

**3. The immune system and its cellular components**

B and T lymphocytes form the arm of the adaptive and antigen-specific immune response. B lymphocytes are antigen presenting cells, upon antigenic and cytokine stimulation they differentiate into plasma cells which produce antigen-specific antibodies. While T lympho‐ cytes are divided into two distinct populations: helper and cytotoxic cells which are differ in their function T helper lymphocytes express the CD4 surface receptor, recognize antigens presented as peptide epitopes bound to MHC class II molecules expressed on the surface of antigen presenting cells, and function mainly as cytokine producing cells to 'help' the devel‐ opment of the immune response. Activated CD4+ T cells differentiate into T helper (Th)-1 and Th-2 effectors, and memory cell sub-populations. The Th-1 and Th-2 subsets of CD4+ T cells were originally defined by their polarized cytokine production patterns [15,16]. Th-1 cells produce IFN-γ, IL-2, IL-12 and lymphotoxin-α, which enhance antigen presentation, phago‐ cytosis, and cell-mediated cytotoxicity. On the other hand, Th-2 cells secrete IL-4, IL-5, IL-9, IL-10, and IL-13, promoting more of an antibody response [16-18]. Cytotoxic T lymphocytes however, express the CD8 surface receptor, and recognize antigenic peptide epitopes present‐ ed on cell surface MHC class I molecules. Antigen-activated CD8+ T cells also proliferate and differentiate into effectors and memory cell populations, largely in response to cytokines that share the common γc receptor, such as IL-2, IL-15, and IL-7. Cytotoxic T cells secrete IFN-γ, which inhibits virus replication, as well as perforin, and granzymes in order to kill virusinfected cells.

#### **3.3. HIV and the cellular immune response**

HIV is commonly transmitted by sexual contact, and thus it initially interacts with and activates the innate immune system and antigen presenting cells including macrophages and dendritic cells at the mucosal surfaces [5,19,20]. Importantly, these cells then migrate to the lymphoid tissues and thereby also deliver the virus to other susceptible cells located at these sites. In the lymphoid tissues, HIV interacts and infects other cells such as CD4+ T cells and is able to disseminate to other areas such as the brain and gut [5,21]. Subsequently, inflammatory cells

and cytokines accumulate during chronic infection and immune activation causing severe reactions and tissue pathology. This includes destruction of regulatory immune cells, mainly CD4+ T cells, and overall impairment of immune functions, which are the hallmarks of chronic HIV infection [5,22-24]. Studies have shown that M/M and T lymphocyte functions are impaired over the course of HIV infection, thus contributing to the overall immune dysfunction and appearance of the opportunistic infections observed in HIV-infected patients. Several *ex vivo* and *in vitro* studies have reported that many M/M defects arise during chronic HIV infection including poor phagocytic activity [25-27], altered cytokine and chemokine secretion [24,28-31], impaired antigen uptake and MHC class II molecule expression [32,33]. Other studies have shown defects in T lymphocyte effector functions including impairment of CD4 T lymphocytes to produce IL-2 and to proliferate in response to recall antigens (influenza, tetanus toxoid), alloantigens (mixed lymphocytes reaction), or exogenous mitogens (phyto‐ hemagglutinin) [34,35]. Also, CD8 T lymphocytes exhibit an altered differentiation and proliferative phenotype and impaired capacity to kill virus-infected cells and clear the virus [36]. However, the molecular mechanism by which HIV impairs these cellular functions remains unclear. One possible mechanism by which chronic HIV infection may adversely affect immune cell function is through the modulation of cell signaling molecules, as observed in several cell types including M/M, CD4+ and CD8+ T cells, and neuronal cells [37-42]. This may occur by the direct action of HIV and its different immunomodulatory proteins such as Gp120, Nef, Tat, and Vpr, or indirectly via its effects on the cytokine secretion profile induced during the course of the disease as discussed in more detail below [43-46].

clearance of extracellular antigens/pathogens [16,50,52]. During chronic HIV infection, both types of immune response and their associated cytokines are dysregulated, which may result in altered M/M and lymphocyte functions and increased susceptibility to programmed cell

The following section will focus on cytokines that play an important role in regulating M/M as well as T lymphocytes effector functions and cell survival. These cytokines include IFN-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-10, IL-4, IL-2, IL-7, and IL-15

**Cytokine Producer cells Effects on M/M, T cells STAT signaling in**

I.

Upregulates the activation of MHC class I and II, and activates pathogen killing.

Upregulates the activation of MHC class

Stimulates growth and differentiation of myelomonocytic lineage cells. Enhances phagocytosis.

Potent suppressor of monocytes/ macrophage function (e.g. inhibits MHC class II activation, antigen presentation,

Induces activation of MHC class II, induces endocytosis, and mannose

Promotes T cell proliferation and T reg

Induces survival and proliferation of CD8 T cells, NK cells and NK T cells.

and phagocytosis).

receptor activation.

Cytokines such as IFN-γ and GM-CSF affect mainly M/M, while, IL-10 and IL-4 act on both M/M and lymphocytes. IFN-γ is an 18-kDa potent pleiotropic cytokine produced by NK cells, NK T cells, Th-1, and CD8+ T cells. It has a critical role in the regulation of both innate and adaptive immunity [57,58]. It inhibits Th-2 and promotes Th-1 cell polarization and differen‐

development

in lymphoid organs Maintains thymocytes survival.

**Table 1.** Cytokines and their effects on monocyte/macrophage and T lymphocyte functions

**viremic patient**

http://dx.doi.org/10.5772/53010

7

Immune Responses and Cell Signaling During Chronic HIV Infection

Increased STAT1 activation

Decreased STAT1 activation

Not significantly affected

Not significantly affected

Not significantly affected

Decreased STAT5 activation

Decreased STAT5 activation

Not significantly affected

death (PCD) [53-56].

(summarized in Table 1).

IFN-γ Th1 lymphocytes, activated NK cells, and CD8 T cells

IFN-α Leukocytes, and virus-infected

cells

GM-CSF T cells, Macrophages

IL-10 T cells, Macrophages

IL-4 Th2 lymphocytes

IL-7

IL-15

IL-2 Activated T lymphocytes and dendritic cells

**4.1. Cytokines that affect monocytes**

Bone marrow and stromal cells

M/M, dendritic cells, mast cells, epithelial cells, and fibroblast

### **4. Cytokines**

As mentioned above, cytokines are small secreted proteins with molecular weights of about 10-40 kDa [18,47,48]. These proteins function as mediators to regulate both the innate and adaptive immune responses [4,6,7]. They transmit the biochemical message from the extrac‐ ellular environment to the nucleus of the targeted cell via cytokine-cytokine receptor interac‐ tion and subsequent triggering of complex intracellular signal transduction [49,50]. They can affect cell function in a paracrine as well as an autocrine manner. There are many cytokines produced by the immune system. Certain cytokines are associated with the initial response to an infection or inflammation and are referred to as inflammatory cytokines. Other cytokines are induced according to the nature of the infectious agent and the type of immune responses produced against them. For instance, infection with *Influenza virus*, *Vaccinia virus*, or *Listeria monocytogenes* is known to induce a Th-1 immune response [51]. This type of immune response is associated with the production of cytokines such as IL-2, IFN-γ, and IL-12, which regulate cell-mediated immunity including delayed hypersensitivity reactions, activation of macro‐ phages and leukocyte cytolytic processes, and result in the protection and elimination of intracellular pathogens [16,50,52]. On the other hand, infection with *Nippostrongylus barsilien‐ sis* or *Leishmania major* is known to induce a Th-2 response [51]. This immune response is characterized by secretion of cytokines such as IL-4, IL-5, IL-9, IL-10, and IL-13 that predom‐ inantly regulate antibody-mediated immunity and generally lead to the protection and clearance of extracellular antigens/pathogens [16,50,52]. During chronic HIV infection, both types of immune response and their associated cytokines are dysregulated, which may result in altered M/M and lymphocyte functions and increased susceptibility to programmed cell death (PCD) [53-56].

The following section will focus on cytokines that play an important role in regulating M/M as well as T lymphocytes effector functions and cell survival. These cytokines include IFN-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-10, IL-4, IL-2, IL-7, and IL-15 (summarized in Table 1).


**Table 1.** Cytokines and their effects on monocyte/macrophage and T lymphocyte functions

#### **4.1. Cytokines that affect monocytes**

and cytokines accumulate during chronic infection and immune activation causing severe reactions and tissue pathology. This includes destruction of regulatory immune cells, mainly CD4+ T cells, and overall impairment of immune functions, which are the hallmarks of chronic HIV infection [5,22-24]. Studies have shown that M/M and T lymphocyte functions are impaired over the course of HIV infection, thus contributing to the overall immune dysfunction and appearance of the opportunistic infections observed in HIV-infected patients. Several *ex vivo* and *in vitro* studies have reported that many M/M defects arise during chronic HIV infection including poor phagocytic activity [25-27], altered cytokine and chemokine secretion [24,28-31], impaired antigen uptake and MHC class II molecule expression [32,33]. Other studies have shown defects in T lymphocyte effector functions including impairment of CD4 T lymphocytes to produce IL-2 and to proliferate in response to recall antigens (influenza, tetanus toxoid), alloantigens (mixed lymphocytes reaction), or exogenous mitogens (phyto‐ hemagglutinin) [34,35]. Also, CD8 T lymphocytes exhibit an altered differentiation and proliferative phenotype and impaired capacity to kill virus-infected cells and clear the virus [36]. However, the molecular mechanism by which HIV impairs these cellular functions remains unclear. One possible mechanism by which chronic HIV infection may adversely affect immune cell function is through the modulation of cell signaling molecules, as observed in several cell types including M/M, CD4+ and CD8+ T cells, and neuronal cells [37-42]. This may occur by the direct action of HIV and its different immunomodulatory proteins such as Gp120, Nef, Tat, and Vpr, or indirectly via its effects on the cytokine secretion profile induced

during the course of the disease as discussed in more detail below [43-46].

As mentioned above, cytokines are small secreted proteins with molecular weights of about 10-40 kDa [18,47,48]. These proteins function as mediators to regulate both the innate and adaptive immune responses [4,6,7]. They transmit the biochemical message from the extrac‐ ellular environment to the nucleus of the targeted cell via cytokine-cytokine receptor interac‐ tion and subsequent triggering of complex intracellular signal transduction [49,50]. They can affect cell function in a paracrine as well as an autocrine manner. There are many cytokines produced by the immune system. Certain cytokines are associated with the initial response to an infection or inflammation and are referred to as inflammatory cytokines. Other cytokines are induced according to the nature of the infectious agent and the type of immune responses produced against them. For instance, infection with *Influenza virus*, *Vaccinia virus*, or *Listeria monocytogenes* is known to induce a Th-1 immune response [51]. This type of immune response is associated with the production of cytokines such as IL-2, IFN-γ, and IL-12, which regulate cell-mediated immunity including delayed hypersensitivity reactions, activation of macro‐ phages and leukocyte cytolytic processes, and result in the protection and elimination of intracellular pathogens [16,50,52]. On the other hand, infection with *Nippostrongylus barsilien‐ sis* or *Leishmania major* is known to induce a Th-2 response [51]. This immune response is characterized by secretion of cytokines such as IL-4, IL-5, IL-9, IL-10, and IL-13 that predom‐ inantly regulate antibody-mediated immunity and generally lead to the protection and

**4. Cytokines**

6 Current Perspectives in HIV Infection

Cytokines such as IFN-γ and GM-CSF affect mainly M/M, while, IL-10 and IL-4 act on both M/M and lymphocytes. IFN-γ is an 18-kDa potent pleiotropic cytokine produced by NK cells, NK T cells, Th-1, and CD8+ T cells. It has a critical role in the regulation of both innate and adaptive immunity [57,58]. It inhibits Th-2 and promotes Th-1 cell polarization and differen‐ tiation. Also, it inhibits viral replication and regulates cell death [57,58]. Moreover, it activates monocytes and macrophages, increases MHC class II expression, promotes antigen processing and presentation, and enhances their phagocytic, antimicrobial, and tumoricidal activities [59-64]. For instance, it has been shown that treatment of M/M with IFN-γ enhanced phagocytic activity against many pathogens including *Aspergillus fumigatus, Cryptococcus neoformans, Listeria monocytogenes, Mycobacterium avium, Toxoplama cruzi and gondii*[26,61,65]. Other studies have revealed that the lack of IFN-γ responses, such as in IFN- γ, IFN-γ receptor (IFN-γR), or STAT1-deficient mice, or in patients with mutations in the IFN-γ-R gene, lead to impaired immunity and increased susceptibility to infection [66-70]. GM-CSF is a 22-kDa protein secreted by macrophages and T cells. It facilitates growth and differentiation of monocyte and granulocyte lineages. It also enhances M/M effector functions including phagocytic, antimi‐ crobial and antiparasitic activities [71,72].

regulating the expression of the pro-apoptotic molecule Bax [102-105]. Thus, it is an essential

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IL-15 is a cytokine that is produced by different cell types including M/M, dendritic cells, mast cells, epithelial cells, and fibroblasts. It plays an important role in growth and homeostasis. It provokes adaptive and innate immune responses. For example, it shares several biological effects with IL-2 such as mediating survival and proliferation of naïve and memory CD8 T cells. It also stimulates NK T cell expansion and regulates the development of NK cells and its

It has been reported that during the course of chronic HIV infection, many inflammatory and anti-inflammatory cytokines such as TNF-α, IFN-β, IFN-γ, IL-18, IL-2, IL-10, and IL-4 are increased in patients serum [77,107-115], and thus may play a role in the alteration of M/M and T lymphocyte functions and signaling pathways (Table 1) [38-42]. Several studies have also proposed and used cytokines such as IFN-γ, GM-CSF, IL-4, IL-2, IL-7 and IL-15 as therapeutics in clinical trials for diseases including HIV and myeloma in an attempt to compensate for

Cytokine signaling pathways can be defined as biochemical signaling cascades that are triggered within minutes to relay the information required to mediate various cytokinedependent cellular functions [119-123]. Most cytokines share general mechanisms of sig‐ nal transduction in which cytokine-cytokine receptor binding causes the assembly of the specific receptor subunits. Subsequently, a number of tyrosine kinases from the Src and Syk families are activated leading to signal transduction through mainly three major sig‐ naling pathways: (i) Janus Kinase (JAK)/Signal Transducer and Activator of Transcription (STAT), (ii) Phosphoinositide 3-kinase (PI3K), and (iii) Mitogen-activated protein kinase (MAPK) [124-126]. These signaling pathways form a very complex and evolutionarily

A general overview of these cascades is illustrated in Figure 1. Briefly, when the ligandreceptor interaction occurs, subsequent events are activated based on the nature of these ligands and receptors. For example, a receptor with intrinsic kinase activity (e.g. epidermal growth factor receptor) is usually autophosphorylated directly leading to the creation of a docking site for an adapter protein complex called Grb2/SOS (son of sevenless) [36]. As a result, SOS is recruited to the plasma membrane where it encounters and activates a small G protein named Ras [36,127,128]. Activated Ras induces the activation of several downstream signaling molecules, including a serine/threonine kinase called Raf, which in turn activates the MAPK and PI3K signaling pathways [36,127,129]. PI3K signaling molecules can also be activated directly via the p110α catalytic subunit of the PI3K [127]. A receptor with no intrinsic kinase activity (e.g. cytokine receptors) generally requires activation of receptor-associated kinases such as JAKs for its phosphorylation. Subsequently, activated JAKs can activate the STAT signaling pathway directly and also interact with and activate Grb2/SOS, which in turn

element for T cell survival, proliferation, and optimal effector function.

impairments in the cytokine network [36,99,116-118].

activates PI3K and MAPK signaling [36,122,130,131].

**4.3. Cytokine signaling pathways**

conserved network.

cytotoxicity [36,99,106].

IL-10 is a potent immunosuppressive and anti-inflammatory cytokine produced by macro‐ phages and T cells. It downregulates MHC class II molecule expression and antigen presen‐ tation to CD4+ T cells [73,74]. It also inhibits the expression of co-stimulatory molecules, B7.1/ B7.2, on monocytes and macrophages as well as the production of various cytokines such as TNF-α, IL-1, IL-2, IFN-γ, IL-3, and GM-CSF [73,75,76]. In addition, it suppresses macrophage nitric oxide production, and anti-fungal activity [77]. Moreover, it stimulates proliferation and differentiation of B cells, and polarizes T cells towards a Th-2 type response [17,78].

IL-4 is a 20-kDa cytokine secreted by Th-2 lymphocytes that promotes a Th-2 immune response. It has dual immunoregulatory functions [18]. It activates B cell differentiation and antibody production. Also, it enhances macrophage cytotoxicity and their expression of MHC class II and mannose receptor [79-84]. On the other hand, it inhibits cytokine secretion such as TNFα, IL-1, IL-6, IL-18, GM-CSF and granulocyte colony-stimulating factor (G-CSF) [85-94]. It also suppresses cytokine-induced macrophage activation, oxidative burst, and intracellular killing [62,95]. Moreover, it downregulates monocyte adhesion and CD14 expression [96,97], mono‐ cyte-mediated cytotoxicity, nitric oxide production, and anti-fungal activity [77,98].

### **4.2. Cytokines that affect lymphocytes**

Cytokines that share the γ-chain receptor, such as IL-2, IL-7, and IL-15, play a critical role in lymphocyte growth and differentiation [36,99]. IL-2 is a protein produced mainly by activated CD4 but also CD8 T lymphocytes and dendritic cells. It is a T cell growth factor and plays a critical role in regulating the immune response. It plays a major role in activating the immune system in the presence of antigenic stimulation, but also in downregulating this response following pathogen clearance. IL-2 stimulates T cell proliferation and is essential for develop‐ ing regulatory T cells. In addition, IL-2 has been shown to upregulate expression of Tumor Necrosis Family death receptor ligand, FasL, in activated T cells thereby enhancing their susceptibility to activation-induced cell death [100,101].

IL-7 is a pleiotropic cytokine secreted by bone marrow and stromal cells of lymphoid organs. It stimulates the growth and maintains the survival of thymocytes (B and T lymphocyte progenitor cells) by increasing the expression of the anti-apoptotic molecule Bcl-2 and downregulating the expression of the pro-apoptotic molecule Bax [102-105]. Thus, it is an essential element for T cell survival, proliferation, and optimal effector function.

IL-15 is a cytokine that is produced by different cell types including M/M, dendritic cells, mast cells, epithelial cells, and fibroblasts. It plays an important role in growth and homeostasis. It provokes adaptive and innate immune responses. For example, it shares several biological effects with IL-2 such as mediating survival and proliferation of naïve and memory CD8 T cells. It also stimulates NK T cell expansion and regulates the development of NK cells and its cytotoxicity [36,99,106].

It has been reported that during the course of chronic HIV infection, many inflammatory and anti-inflammatory cytokines such as TNF-α, IFN-β, IFN-γ, IL-18, IL-2, IL-10, and IL-4 are increased in patients serum [77,107-115], and thus may play a role in the alteration of M/M and T lymphocyte functions and signaling pathways (Table 1) [38-42]. Several studies have also proposed and used cytokines such as IFN-γ, GM-CSF, IL-4, IL-2, IL-7 and IL-15 as therapeutics in clinical trials for diseases including HIV and myeloma in an attempt to compensate for impairments in the cytokine network [36,99,116-118].

### **4.3. Cytokine signaling pathways**

tiation. Also, it inhibits viral replication and regulates cell death [57,58]. Moreover, it activates monocytes and macrophages, increases MHC class II expression, promotes antigen processing and presentation, and enhances their phagocytic, antimicrobial, and tumoricidal activities [59-64]. For instance, it has been shown that treatment of M/M with IFN-γ enhanced phagocytic activity against many pathogens including *Aspergillus fumigatus, Cryptococcus neoformans, Listeria monocytogenes, Mycobacterium avium, Toxoplama cruzi and gondii*[26,61,65]. Other studies have revealed that the lack of IFN-γ responses, such as in IFN- γ, IFN-γ receptor (IFN-γR), or STAT1-deficient mice, or in patients with mutations in the IFN-γ-R gene, lead to impaired immunity and increased susceptibility to infection [66-70]. GM-CSF is a 22-kDa protein secreted by macrophages and T cells. It facilitates growth and differentiation of monocyte and granulocyte lineages. It also enhances M/M effector functions including phagocytic, antimi‐

IL-10 is a potent immunosuppressive and anti-inflammatory cytokine produced by macro‐ phages and T cells. It downregulates MHC class II molecule expression and antigen presen‐ tation to CD4+ T cells [73,74]. It also inhibits the expression of co-stimulatory molecules, B7.1/ B7.2, on monocytes and macrophages as well as the production of various cytokines such as TNF-α, IL-1, IL-2, IFN-γ, IL-3, and GM-CSF [73,75,76]. In addition, it suppresses macrophage nitric oxide production, and anti-fungal activity [77]. Moreover, it stimulates proliferation and

IL-4 is a 20-kDa cytokine secreted by Th-2 lymphocytes that promotes a Th-2 immune response. It has dual immunoregulatory functions [18]. It activates B cell differentiation and antibody production. Also, it enhances macrophage cytotoxicity and their expression of MHC class II and mannose receptor [79-84]. On the other hand, it inhibits cytokine secretion such as TNFα, IL-1, IL-6, IL-18, GM-CSF and granulocyte colony-stimulating factor (G-CSF) [85-94]. It also suppresses cytokine-induced macrophage activation, oxidative burst, and intracellular killing [62,95]. Moreover, it downregulates monocyte adhesion and CD14 expression [96,97], mono‐

Cytokines that share the γ-chain receptor, such as IL-2, IL-7, and IL-15, play a critical role in lymphocyte growth and differentiation [36,99]. IL-2 is a protein produced mainly by activated CD4 but also CD8 T lymphocytes and dendritic cells. It is a T cell growth factor and plays a critical role in regulating the immune response. It plays a major role in activating the immune system in the presence of antigenic stimulation, but also in downregulating this response following pathogen clearance. IL-2 stimulates T cell proliferation and is essential for develop‐ ing regulatory T cells. In addition, IL-2 has been shown to upregulate expression of Tumor Necrosis Family death receptor ligand, FasL, in activated T cells thereby enhancing their

IL-7 is a pleiotropic cytokine secreted by bone marrow and stromal cells of lymphoid organs. It stimulates the growth and maintains the survival of thymocytes (B and T lymphocyte progenitor cells) by increasing the expression of the anti-apoptotic molecule Bcl-2 and down-

differentiation of B cells, and polarizes T cells towards a Th-2 type response [17,78].

cyte-mediated cytotoxicity, nitric oxide production, and anti-fungal activity [77,98].

crobial and antiparasitic activities [71,72].

8 Current Perspectives in HIV Infection

**4.2. Cytokines that affect lymphocytes**

susceptibility to activation-induced cell death [100,101].

Cytokine signaling pathways can be defined as biochemical signaling cascades that are triggered within minutes to relay the information required to mediate various cytokinedependent cellular functions [119-123]. Most cytokines share general mechanisms of sig‐ nal transduction in which cytokine-cytokine receptor binding causes the assembly of the specific receptor subunits. Subsequently, a number of tyrosine kinases from the Src and Syk families are activated leading to signal transduction through mainly three major sig‐ naling pathways: (i) Janus Kinase (JAK)/Signal Transducer and Activator of Transcription (STAT), (ii) Phosphoinositide 3-kinase (PI3K), and (iii) Mitogen-activated protein kinase (MAPK) [124-126]. These signaling pathways form a very complex and evolutionarily conserved network.

A general overview of these cascades is illustrated in Figure 1. Briefly, when the ligandreceptor interaction occurs, subsequent events are activated based on the nature of these ligands and receptors. For example, a receptor with intrinsic kinase activity (e.g. epidermal growth factor receptor) is usually autophosphorylated directly leading to the creation of a docking site for an adapter protein complex called Grb2/SOS (son of sevenless) [36]. As a result, SOS is recruited to the plasma membrane where it encounters and activates a small G protein named Ras [36,127,128]. Activated Ras induces the activation of several downstream signaling molecules, including a serine/threonine kinase called Raf, which in turn activates the MAPK and PI3K signaling pathways [36,127,129]. PI3K signaling molecules can also be activated directly via the p110α catalytic subunit of the PI3K [127]. A receptor with no intrinsic kinase activity (e.g. cytokine receptors) generally requires activation of receptor-associated kinases such as JAKs for its phosphorylation. Subsequently, activated JAKs can activate the STAT signaling pathway directly and also interact with and activate Grb2/SOS, which in turn activates PI3K and MAPK signaling [36,122,130,131].

activate phospholipase Cγ (PLCγ), which activate Protein Kinase C (PKC) and calcium-dependent signaling pathways. If the receptor has no intrinsic kinase activity, activation of the Janus Kinase (Jak) or other receptor-associated kinase occurs. Subsequently, activated Jaks phosphorylate the receptor and thus create docking sites for various signaling molecules including members of the Signal Transducers and Activators of Transcription (STAT) family. Signal transduc‐ tion culminates in the transcriptional activation of STAT responsive genes that influence cellular proliferation, differen‐

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Evidence has also demonstrated the presence of a complex crosstalk between these pathways. For instance, it has been shown that Jak2 is responsible for the activation of STAT, Erk MAPK, and Akt signaling pathways in response to growth hormone in hepatoma and preadipocyte cells [132]. Another report has demonstrated a role for Akt in serine phosphorylation of the STAT1 transcription factor and upregulation of gene expression in response to IFN-γ [133].

HIV-induced perturbation of the JAK/STAT, PI3K, and MAPK signaling pathways in immune cells including M/M and T lymphocytes has been documented (summarized in Table 1, 4) [41,134-146]. These effects appear to be to the advantage of the virus. On one hand, it may help the virus to replicate and establish infection. On the other hand, it may also help the virus to escape the immune system. In the following subsections, we will provide a brief overview of

The JAK/STAT pathway is one of the major signaling pathways involved in cytokine responses. Studies have shown that many ligands such as epidermal growth factor (EGF), receptor tyrosine kinases (RTK), G protein-coupled receptors (GPCR) and several cytokine families including interferons and interleukins are the main triggers of the JAK/STAT signaling cascade [147-149]. An overview of the JAK/STAT signal transduction pathway is illustrated in Figure 1. Initially, cytokine-receptor interaction triggers tyrosine transphosphorylation of receptorassociated JAKs. This is followed by phosphorylation of receptor cytoplasmic domains by JAKs and recruitment of latent STAT proteins via their Src homology 2 (SH2) domains to the activated (tyrosine phosphorylated) receptor. This is followed by STAT tyrosine phosphory‐ lation. Activated STATs form dimers via their SH2 domains and are translocated into the nucleus where they bind STAT responsive elements [119,120,123], and thus promote tran‐ scription of STAT responsive genes such as cytokine-inducible SH2-containing protein (CIS),

In mammalian cells, four JAKs (Jak1, Jak2, Jak3 and Tyk2) and seven STAT proteins (STAT1, 2, 3, 4, 5a, 5b, and 6) with their different isoforms have been identified. [147,154]. Through IL-6-induced signaling, Jak1 is the principal kinase in the downstream signaling cascade. It has been shown in many cell lines that down regulation of Jak1 would lead to impaired signal transduction. Activated JAKs lead to phosphorylation of STAT proteins. However, JAK kinases do not appear to show specificity for a particular STAT protein [147,154]. STAT proteins play an important role in regulating and main‐ taining both innate and adaptive immune responses (summarized in Table 2) [119-121,123]. For instance, studies have suggested that impairment of JAK/STAT signal‐

ing may increase susceptibility to many infections including HIV [65,67,70,155].

cytokine signaling and where HIV infection appears to target these cascades.

members of the IRF family, and numerous other genes [150-153].

*4.3.1. JAK/STAT signaling pathway*

tiation, cytokine production, mobility, phagocytosis, and survival [modified from [187]].

**Figure 1. Overview of the major intracellular signaling pathways** Upon ligand-receptor binding, signal transduc‐ tion triggers takes place based on the type and nature of the receptor. If the receptor has intrinsic tyrosine kinase ac‐ tivity, autophosphorylation of the tyrosine residues of the receptor will occur and thus creates docking sites for a variety of different signaling molecules that have SH2 and PTB domains. Grb2/SOS complexes bind to docking sites and lead to recruitment of SOS (son of sevenless) to the plasma membrane where they interact with Ras. Subsequent‐ ly, activated Ras molecules activate several downstream molecules including Raf, MAPKK, and MAPK. The PI3K signal‐ ing pathway can be activated directly via the p110α catalytic subunit of the PI3K. Phosphorylated receptors also activate phospholipase Cγ (PLCγ), which activate Protein Kinase C (PKC) and calcium-dependent signaling pathways. If the receptor has no intrinsic kinase activity, activation of the Janus Kinase (Jak) or other receptor-associated kinase occurs. Subsequently, activated Jaks phosphorylate the receptor and thus create docking sites for various signaling molecules including members of the Signal Transducers and Activators of Transcription (STAT) family. Signal transduc‐ tion culminates in the transcriptional activation of STAT responsive genes that influence cellular proliferation, differen‐ tiation, cytokine production, mobility, phagocytosis, and survival [modified from [187]].

Evidence has also demonstrated the presence of a complex crosstalk between these pathways. For instance, it has been shown that Jak2 is responsible for the activation of STAT, Erk MAPK, and Akt signaling pathways in response to growth hormone in hepatoma and preadipocyte cells [132]. Another report has demonstrated a role for Akt in serine phosphorylation of the STAT1 transcription factor and upregulation of gene expression in response to IFN-γ [133].

HIV-induced perturbation of the JAK/STAT, PI3K, and MAPK signaling pathways in immune cells including M/M and T lymphocytes has been documented (summarized in Table 1, 4) [41,134-146]. These effects appear to be to the advantage of the virus. On one hand, it may help the virus to replicate and establish infection. On the other hand, it may also help the virus to escape the immune system. In the following subsections, we will provide a brief overview of cytokine signaling and where HIV infection appears to target these cascades.

### *4.3.1. JAK/STAT signaling pathway*

**Figure 1. Overview of the major intracellular signaling pathways** Upon ligand-receptor binding, signal transduc‐ tion triggers takes place based on the type and nature of the receptor. If the receptor has intrinsic tyrosine kinase ac‐ tivity, autophosphorylation of the tyrosine residues of the receptor will occur and thus creates docking sites for a variety of different signaling molecules that have SH2 and PTB domains. Grb2/SOS complexes bind to docking sites and lead to recruitment of SOS (son of sevenless) to the plasma membrane where they interact with Ras. Subsequent‐ ly, activated Ras molecules activate several downstream molecules including Raf, MAPKK, and MAPK. The PI3K signal‐ ing pathway can be activated directly via the p110α catalytic subunit of the PI3K. Phosphorylated receptors also

10 Current Perspectives in HIV Infection

The JAK/STAT pathway is one of the major signaling pathways involved in cytokine responses. Studies have shown that many ligands such as epidermal growth factor (EGF), receptor tyrosine kinases (RTK), G protein-coupled receptors (GPCR) and several cytokine families including interferons and interleukins are the main triggers of the JAK/STAT signaling cascade [147-149]. An overview of the JAK/STAT signal transduction pathway is illustrated in Figure 1. Initially, cytokine-receptor interaction triggers tyrosine transphosphorylation of receptorassociated JAKs. This is followed by phosphorylation of receptor cytoplasmic domains by JAKs and recruitment of latent STAT proteins via their Src homology 2 (SH2) domains to the activated (tyrosine phosphorylated) receptor. This is followed by STAT tyrosine phosphory‐ lation. Activated STATs form dimers via their SH2 domains and are translocated into the nucleus where they bind STAT responsive elements [119,120,123], and thus promote tran‐ scription of STAT responsive genes such as cytokine-inducible SH2-containing protein (CIS), members of the IRF family, and numerous other genes [150-153].

In mammalian cells, four JAKs (Jak1, Jak2, Jak3 and Tyk2) and seven STAT proteins (STAT1, 2, 3, 4, 5a, 5b, and 6) with their different isoforms have been identified. [147,154]. Through IL-6-induced signaling, Jak1 is the principal kinase in the downstream signaling cascade. It has been shown in many cell lines that down regulation of Jak1 would lead to impaired signal transduction. Activated JAKs lead to phosphorylation of STAT proteins. However, JAK kinases do not appear to show specificity for a particular STAT protein [147,154]. STAT proteins play an important role in regulating and main‐ taining both innate and adaptive immune responses (summarized in Table 2) [119-121,123]. For instance, studies have suggested that impairment of JAK/STAT signal‐ ing may increase susceptibility to many infections including HIV [65,67,70,155].


*4.3.2. PI3K signaling pathway*

infected macrophages [167].

**Target Gene Phenotype**

P110<sup>β</sup> Embryonic lethal

SHIP2 Perinatal lethal

**Table 3.** Characteristics of PI3K knockout mice

p85<sup>β</sup> Increased insulin sensitivity

p110<sup>α</sup> Embryonic lethal and defective proliferation

and oxidative burst

activation, and chemotaxis

been identified named *akt1*, *akt2*, and *akt3*.

Phosphoinositide 3-kinases or phosphatidylinositol-3-kinases (PI3Ks) belong to a family of enzymes that have serine/threonine kinase activity. These enzymes can be activated by various stimuli including growth factors, antigens, cytokines [157,158], and are capable of phosphor‐ ylating the third position hydroxyl group of the inositol ring of phosphatidylinositol (PtdIns) [157,159]. This family is composed of four classes, which differ in their structure and functions (known as Ia, Ib, II, and III). However, all of them contain at least one catalytic domain and one regulatory domain [157,159]. Many PI3K cellular functions rely on the ability of PI3Ks to activate protein kinase B (PKB, also known as Akt) (Figure 1). In humans, three Akt genes have

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PI3-kinases have been shown to play a major role in diverse cellular functions, including cell growth, proliferation, differentiation, survival, and migration [160-163]. Thus, dysregulation of this pathway may influence different cellular responses that are associated with immunity as well as carcinogenesis (Table 3) [157,164]. It has also been reported that there is a basal activation of the PI3K/Akt pathways in macrophages that is required for their survival [165]. Certain reports have suggested a critical role for PI3K signaling in chronic immune activation by promoting cell survival [166]. For instance, an *in vitro* study has revealed that HIV infection and its protein Tat was sufficient to activate the PI3K/Akt pathway in macrophages [166]. Interestingly, PI3K/Akt inhibitors including Miltefosine, an antiprotozoal drug known to inhibit PI3K/Akt pathway, significantly reduced HIV-1 production from infected macrophages and increased susceptibility to cell death in response to extracellular stress, as compared to uninfected cells [166]. Another study has shown that inhibition of Akt phosphorylation is required for TNF related apoptosis inducing ligand (TRAIL)-induced cell death in HIV

p85<sup>α</sup> Decreased B cell development and activation, increased antiviral responses

P110<sup>γ</sup> Decreased T cell development and activation, decreased inflammation, chemotaxis,

PTEN Embryonic lethal, autoimmune disease, decreased T cell development, increased T cell

SHIP1 Increased myeloid cell proliferation and survival, increased B cell activation, chemotaxis, and mast cell degranulation

**Table 2.** STATs proteins and their role in the immune system

A number of reports have suggested that defects in cytokine responsiveness arise in different cell types during chronic HIV infection and these defects could be due to the direct effects of HIV and/or its proteins, or due to indirect effects associated with alterations of the host cytokine profile [38-42,139,141-143,156]. In M/M, it has been revealed that GM-CSF-induced STAT5 activation in monocyte-derived macrophages (MDM) is inhibited by *in vitro* HIV-1 infection [156]. Other *in vitro* reports have suggested that HIV and its Gp120 and Nef proteins are capable of activating STAT1 and STAT3 in monocytic cell lines and MDM [141-143]. Recently, the HIV matrix protein p17 has been shown to induce STAT1 and pro-inflammatory cytokines in macrophages [139]. Moreover, in *ex* vivo studies, we found that among the responses to cytokines tested (IFN-γ, IFN-α, IL-10, IL-4, and GM-CSF) in terms of STAT induction in monocytes, only IFN-γ showed a significant upregulation of STAT1 activation in HIV+ patients that were off antiretroviral therapy (ART) compared to HIV- controls and patients on ART [39]. Furthermore, this potentiation of IFN-γ-induced STAT1 activation was associated with increased total STAT1 expression levels and monocyte cell death [39]. Another *ex vivo* study has shown a defect in IFN-α induced STAT1 activation in monocytes obtained from a similar set of HIV patients, and this defect was due to the decreased IFN-α receptor expression levels on these cells [42].

In lymphocytes, we and others have shown that both IL-7Rα expression and IL-7-induced STAT5 activation was impaired in CD8 T cells from HIV+ patients [36,40,41]. STAT activation in response to IL-4 and IL-10 did not appear to be similarly impaired [40]. We also found that IL-2 induced STAT5 activation was inhibited in CD8+ T cells from a subset of HIV-infected patients naive to therapy, but was restored, at least in part, after ART [38]. Somewhat similar results have been observed in other *in vitro* studies in which activation of STAT5 in response to IL-2 was in‐ hibited by HIV-1 infection through prior Gp120-CD4 interactions in CD4+ T cells [37,144].

### *4.3.2. PI3K signaling pathway*

**STAT gene**

STAT1 IFNs,IL-6,IL-10

12 Current Perspectives in HIV Infection

STAT3 IL-2,IL-6,IL-10

CSF)

on these cells [42].

STAT5 a, b Numerous (e.g. IL-2,IL-7,IL-15, GM-

**Table 2.** STATs proteins and their role in the immune system

**Activating cytokines Examples of STAT**

STAT4 IL-12 IFN-γ, IRF-1, MHC class

**responsive genes Phenotype of knockout mice**

infections

reactive protein, Bcl-xL Embryonic lethal

Impaired IFN and innate immune responses, increase susceptibility to tumors, opportunistic and viral

Defect in IL-4 and IL-12 responses, and

Impaired proliferation, growth and survival, defect in IL-2 responses,

impaired Th1 differentiation.

impaired growth.

Th1 differentiation.

IRF-1, ISG54, MIG, GBP,

JunB, SAA3, JAB, C-

II, CD23, Fc-γRI

STAT6 IL-4,IL-13 IL-4R-α, C-γ-1, C-γ-4 Defect in IL-4 responses, and impaired

A number of reports have suggested that defects in cytokine responsiveness arise in different cell types during chronic HIV infection and these defects could be due to the direct effects of HIV and/or its proteins, or due to indirect effects associated with alterations of the host cytokine profile [38-42,139,141-143,156]. In M/M, it has been revealed that GM-CSF-induced STAT5 activation in monocyte-derived macrophages (MDM) is inhibited by *in vitro* HIV-1 infection [156]. Other *in vitro* reports have suggested that HIV and its Gp120 and Nef proteins are capable of activating STAT1 and STAT3 in monocytic cell lines and MDM [141-143]. Recently, the HIV matrix protein p17 has been shown to induce STAT1 and pro-inflammatory cytokines in macrophages [139]. Moreover, in *ex* vivo studies, we found that among the responses to cytokines tested (IFN-γ, IFN-α, IL-10, IL-4, and GM-CSF) in terms of STAT induction in monocytes, only IFN-γ showed a significant upregulation of STAT1 activation in HIV+ patients that were off antiretroviral therapy (ART) compared to HIV- controls and patients on ART [39]. Furthermore, this potentiation of IFN-γ-induced STAT1 activation was associated with increased total STAT1 expression levels and monocyte cell death [39]. Another *ex vivo* study has shown a defect in IFN-α induced STAT1 activation in monocytes obtained from a similar set of HIV patients, and this defect was due to the decreased IFN-α receptor expression levels

In lymphocytes, we and others have shown that both IL-7Rα expression and IL-7-induced STAT5 activation was impaired in CD8 T cells from HIV+ patients [36,40,41]. STAT activation in response to IL-4 and IL-10 did not appear to be similarly impaired [40]. We also found that IL-2 induced STAT5 activation was inhibited in CD8+ T cells from a subset of HIV-infected patients naive to therapy, but was restored, at least in part, after ART [38]. Somewhat similar results have been observed in other *in vitro* studies in which activation of STAT5 in response to IL-2 was in‐ hibited by HIV-1 infection through prior Gp120-CD4 interactions in CD4+ T cells [37,144].

CIS, IL-2R-α, β-casein, osm, pim1, p21

CIITA

STAT2 IFNs IRF-1, ISG54 Impaired Type-1 IFN responses

Phosphoinositide 3-kinases or phosphatidylinositol-3-kinases (PI3Ks) belong to a family of enzymes that have serine/threonine kinase activity. These enzymes can be activated by various stimuli including growth factors, antigens, cytokines [157,158], and are capable of phosphor‐ ylating the third position hydroxyl group of the inositol ring of phosphatidylinositol (PtdIns) [157,159]. This family is composed of four classes, which differ in their structure and functions (known as Ia, Ib, II, and III). However, all of them contain at least one catalytic domain and one regulatory domain [157,159]. Many PI3K cellular functions rely on the ability of PI3Ks to activate protein kinase B (PKB, also known as Akt) (Figure 1). In humans, three Akt genes have been identified named *akt1*, *akt2*, and *akt3*.

PI3-kinases have been shown to play a major role in diverse cellular functions, including cell growth, proliferation, differentiation, survival, and migration [160-163]. Thus, dysregulation of this pathway may influence different cellular responses that are associated with immunity as well as carcinogenesis (Table 3) [157,164]. It has also been reported that there is a basal activation of the PI3K/Akt pathways in macrophages that is required for their survival [165]. Certain reports have suggested a critical role for PI3K signaling in chronic immune activation by promoting cell survival [166]. For instance, an *in vitro* study has revealed that HIV infection and its protein Tat was sufficient to activate the PI3K/Akt pathway in macrophages [166]. Interestingly, PI3K/Akt inhibitors including Miltefosine, an antiprotozoal drug known to inhibit PI3K/Akt pathway, significantly reduced HIV-1 production from infected macrophages and increased susceptibility to cell death in response to extracellular stress, as compared to uninfected cells [166]. Another study has shown that inhibition of Akt phosphorylation is required for TNF related apoptosis inducing ligand (TRAIL)-induced cell death in HIV infected macrophages [167].


**Table 3.** Characteristics of PI3K knockout mice


**Table 4.** HIV viral proteins and their effects on monocytes/macrophages and lymphocytes

#### *4.3.3. MAPK signaling pathway*

Mitogen-activated protein kinases (MAPKs) are also a family of enzymes that have serine/ threonine kinase activity [168]. This family of kinases is generally activated in response to vari‐ ous extracellular stimuli such as growth factors and inflammatory signals, as well as cellular stress. They regulate different cellular processes including mitosis, proliferation, differentia‐ tion, and cell death [168]. The MAPK family is composed of three major subfamilies of kinases known as the extracellular receptor kinases (ERKs), the c-Jun N-terminal kinases/stress-activat‐ ed protein kinases (JNK/SAPK) and the p38 MAP kinases [169]. Activation of a specific MAP kinase requires activation of a small GTP binding protein (e.g. Ras) which results in the phos‐ phorylation of a series of downstream kinases (Figure 1) [128]. Activation of the MAPK kinase kinase (MAPKKK) (e.g. Raf) leads to the activation of downstream MAPK kinase (MAPKK), and finally, specific MAPK (p38, Erk or JNK) [170,171]. The Erk MAPK family is found in two isoforms called Erk1 and Erk2. Both isoforms are phosphorylated by members of the MEK fami‐ ly, which are often activated by extracellular stimuli such as growth factors, LPS and chemo‐ therapeutic agents [129,172,173]. The JNK family is found in three isoforms named JNK1, JNK2, and JNK3 [174], while the P38 family is found in five different isoforms called p38 (SAPK2), p38β, p38β2, p38γ (SAPK3), and p38δ [175,176]. Both JNK and p38 MAPKs are phosphorylated by SAPK/Erk kinases (SEKs) and mitogen-activated protein kinase kinases (MKKs), which are usually induced by inflammatory cytokines as well as other stressors such as endotoxins, reac‐ tive oxygen species, protein synthesis inhibitors, and ultraviolet (UV) irradiation [174,177-179]. MAPKs have been shown to activate various downstream transcription factors such as activa‐ tor transcription factor (ATF)-2, SP-1 (a member of Specificity Protein/Krüppel-like Factor fami‐ ly) and activator protein (AP)-1, and even STAT3 [178,180-182].

Several reports have shown that activation of the MAPKs resulted in phosphorylation of HIV Rev, Tat, Nef, and p17 proteins and enhanced viral replication [140,183]. Other studies have demonstrated a role for MAPK in regulating monocyte and lymphocyte functions and cell death during HIV infection. For example, in monocytes, it has been shown that the HIV Tat protein stimulates IL-10 production via activation of calcium/MAPK signaling pathways in human monocytes [134,135,184]. Another report has suggested that HIV Vpr is capable of inducing programmed cell death in primary monocytes and the monocytic cell line THP-1 cells [185]. Further, it has been shown that HIV and its protein nef induced FasL, Programmed Death-1 expression and apoptosis in peripheral blood mononuclear cells (PBMCs) and the Jurkat T cell line through activation of the p38 MAPK signaling pathway [138,186].

**Figure 2. A model for the effect of chronic HIV infection on cellular signal transduction** Cell signaling molecules may be regulated directly or indirectly during chronic HIV infection. In the direct setting, HIV and its proteins (Gp120, Nef, Tat, Vpr), through the binding of cellular receptors or internalization by endocytosis, alter signaling pathways in‐ cluding JAK/STAT, PI3K, and MAPK. In the indirect scenario, HIV infection may adversely affects the host cytokine net‐ work, which may in turn affect signal transduction. Both scenarios may thus promote viral replication and defective

Immune Responses and Cell Signaling During Chronic HIV Infection

http://dx.doi.org/10.5772/53010

15

It is well established that HIV targets the immune system and mainly immune cells that express the CD4 surface receptor, but the virus is not exclusive to these cells. Thus, through the course

host immune effector functions and reduce immune cell survival [modified from [187].

**5. Conclusion**

**Figure 2. A model for the effect of chronic HIV infection on cellular signal transduction** Cell signaling molecules may be regulated directly or indirectly during chronic HIV infection. In the direct setting, HIV and its proteins (Gp120, Nef, Tat, Vpr), through the binding of cellular receptors or internalization by endocytosis, alter signaling pathways in‐ cluding JAK/STAT, PI3K, and MAPK. In the indirect scenario, HIV infection may adversely affects the host cytokine net‐ work, which may in turn affect signal transduction. Both scenarios may thus promote viral replication and defective host immune effector functions and reduce immune cell survival [modified from [187].

### **5. Conclusion**

**Viral protein Effects on M/M Effects on lymphocytes** gp120 Stimulates STAT1 activation Stimulates STAT1 activation

Tat Stimulates MAPK, Akt activation Stimulates Akt, MAPK activation Nef Stimulates STAT1 & 3, MAPK activation Stimulates Erk & p38 MAPK activation

Mitogen-activated protein kinases (MAPKs) are also a family of enzymes that have serine/ threonine kinase activity [168]. This family of kinases is generally activated in response to vari‐ ous extracellular stimuli such as growth factors and inflammatory signals, as well as cellular stress. They regulate different cellular processes including mitosis, proliferation, differentia‐ tion, and cell death [168]. The MAPK family is composed of three major subfamilies of kinases known as the extracellular receptor kinases (ERKs), the c-Jun N-terminal kinases/stress-activat‐ ed protein kinases (JNK/SAPK) and the p38 MAP kinases [169]. Activation of a specific MAP kinase requires activation of a small GTP binding protein (e.g. Ras) which results in the phos‐ phorylation of a series of downstream kinases (Figure 1) [128]. Activation of the MAPK kinase kinase (MAPKKK) (e.g. Raf) leads to the activation of downstream MAPK kinase (MAPKK), and finally, specific MAPK (p38, Erk or JNK) [170,171]. The Erk MAPK family is found in two isoforms called Erk1 and Erk2. Both isoforms are phosphorylated by members of the MEK fami‐ ly, which are often activated by extracellular stimuli such as growth factors, LPS and chemo‐ therapeutic agents [129,172,173]. The JNK family is found in three isoforms named JNK1, JNK2, and JNK3 [174], while the P38 family is found in five different isoforms called p38 (SAPK2), p38β, p38β2, p38γ (SAPK3), and p38δ [175,176]. Both JNK and p38 MAPKs are phosphorylated by SAPK/Erk kinases (SEKs) and mitogen-activated protein kinase kinases (MKKs), which are usually induced by inflammatory cytokines as well as other stressors such as endotoxins, reac‐ tive oxygen species, protein synthesis inhibitors, and ultraviolet (UV) irradiation [174,177-179]. MAPKs have been shown to activate various downstream transcription factors such as activa‐ tor transcription factor (ATF)-2, SP-1 (a member of Specificity Protein/Krüppel-like Factor fami‐

Several reports have shown that activation of the MAPKs resulted in phosphorylation of HIV Rev, Tat, Nef, and p17 proteins and enhanced viral replication [140,183]. Other studies have demonstrated a role for MAPK in regulating monocyte and lymphocyte functions and cell death during HIV infection. For example, in monocytes, it has been shown that the HIV Tat protein stimulates IL-10 production via activation of calcium/MAPK signaling pathways in human monocytes [134,135,184]. Another report has suggested that HIV Vpr is capable of inducing programmed cell death in primary monocytes and the monocytic cell line THP-1 cells [185]. Further, it has been shown that HIV and its protein nef induced FasL, Programmed Death-1 expression and apoptosis in peripheral blood mononuclear cells (PBMCs) and the

Jurkat T cell line through activation of the p38 MAPK signaling pathway [138,186].

Inhibits STAT5 activation, Stimulates STAT1,

MAPK activation

p17 Stimulates STAT1 activation No report

Vpr Stimulates MAPK activation No report

ly) and activator protein (AP)-1, and even STAT3 [178,180-182].

**Table 4.** HIV viral proteins and their effects on monocytes/macrophages and lymphocytes

HIV infection Inhibits STAT5 activation, Stimulates STAT1, Akt

activation

*4.3.3. MAPK signaling pathway*

14 Current Perspectives in HIV Infection

It is well established that HIV targets the immune system and mainly immune cells that express the CD4 surface receptor, but the virus is not exclusive to these cells. Thus, through the course of chronic HIV infection the immune system becomes progressively impaired and unable to protect the body from opportunistic pathogens. This impairment not only includes CD4 T cell depletion, but also the dysregulation of immune cell effector functions, and a skewed cytokine/ chemokine expression profile. These effects may be due to the disruption of the described signaling pathways as a result of direct HIV infection, through the action of numerous viral proteins and/or the chronic, but defective state of host immune activation, as summarized in Figure 2. Understanding the molecular mechanisms and identifying the key molecules involved in this impairment may provide important insight towards developing new thera‐ peutic strategies aimed at prolonging the life span of HIV infected individuals and clearing HIV from the host.

[5] Levy JA. Pathogenesis of human immunodeficiency virus infection. Microbiol Rev

Immune Responses and Cell Signaling During Chronic HIV Infection

http://dx.doi.org/10.5772/53010

17

[6] Delves PJ, Roitt IM. The immune system. Second of two parts. N Engl J Med 2000 Jul

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### **Author details**

Abdulkarim Alhetheel1\*, Mahmoud Aly2 and Marko Kryworuchko3

\*Address all correspondence to: abdulkarimfahad@hotmail.com or aalhetheel@ksu.edu.sa

1 Department of Microbiology, Faculty of Medicine, King Saud University, Riyadh, Saudi Arabia

2 King Abdullah International Medical Research Center, National Guard Hospital, Riyadh, Saudi Arabia

3 Department of Veterinary Microbiology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Canada

### **References**


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of chronic HIV infection the immune system becomes progressively impaired and unable to protect the body from opportunistic pathogens. This impairment not only includes CD4 T cell depletion, but also the dysregulation of immune cell effector functions, and a skewed cytokine/ chemokine expression profile. These effects may be due to the disruption of the described signaling pathways as a result of direct HIV infection, through the action of numerous viral proteins and/or the chronic, but defective state of host immune activation, as summarized in Figure 2. Understanding the molecular mechanisms and identifying the key molecules involved in this impairment may provide important insight towards developing new thera‐ peutic strategies aimed at prolonging the life span of HIV infected individuals and clearing

and Marko Kryworuchko3

\*Address all correspondence to: abdulkarimfahad@hotmail.com or aalhetheel@ksu.edu.sa

1 Department of Microbiology, Faculty of Medicine, King Saud University, Riyadh, Saudi

2 King Abdullah International Medical Research Center, National Guard Hospital, Riyadh,

3 Department of Veterinary Microbiology, Western College of Veterinary Medicine, University

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**Chapter 2**

**Role of Dendritic Cell Subsets on HIV-Specific Immunity**

DC are key regulators of immunity in view of the fact that they are involved in immune re‐ sponses against infectious diseases, allergy and cancer [1, 2]. Ralph Steinman was awarded the Nobel Prize for Medicine 2011 for DC discovery in 1973 [3]. Steinman and Cohn [3] de‐ scribed a novel cell type in mouse spleen, which they named ´dendritic cell´ due to their tree-like shape. The major function of DC is the induction of adaptive immunity in the LN.Yet, DC can also interact with innate immune cells, for instance natural killer (NK) and

Upon entry of HIV into the host, the virus has to be transported from mucosal surfaces to lymphatic tissues, where it is transmitted to its primary targets, CD4+ T lymphocytes. This

DC thereby play critical roles during HIV and SIV (simian immunodeficiency virus) infection. The skin and mucosa are composed of two compartments, the epidermis and the dermis (skin) or stratified squamous epithelium and lamina propria (mucosa), each containing a major subset of DC - Langerhans cells (LC) reside in the suprabasal layers of the epidermis and epithelia [5], while dermal/interstitial DC are distributed throughout the connective tis‐

Both subsets represent immature DC that are very efficient in Ag uptake and processing. As immature DC (iDC), they reside in peripheral tissue, which they survey for invading patho‐ gens. Upon encounter with antigen (Ag), DC mature (mDC) and migrate to the draining lymph nodes (LN). They pass through different maturation stages, which enable them to fulfill specific tasks such as the uptake, the processing and the presentation of Ag on major histocompatiblity complex (MHC) molecules to naïve T cells. In the T cell area of lymphatic

> © 2013 Posch et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

Wilfried Posch, Cornelia Lass-Flörl and

Additional information is available at the end of the chapter

Doris Wilflingseder

**1. Introduction**

NKT cells [1, 4].

sue of the dermis [6, 7].

process is thought to be contrived by DC.

http://dx.doi.org/10.5772/52744


### **Role of Dendritic Cell Subsets on HIV-Specific Immunity**

Wilfried Posch, Cornelia Lass-Flörl and Doris Wilflingseder

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/52744

**1. Introduction**

[180] Chung J, Uchida E, Grammer TC, Blenis J. STAT3 serine phosphorylation by ERKdependent and -independent pathways negatively modulates its tyrosine phosphor‐

[181] Hibi M, Lin A, Smeal T, Minden A, Karin M. Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain.

[182] Zhang S, Liu H, Liu J, Tse CA, Dragunow M, Cooper GJ. Activation of activating transcription factor 2 by p38 MAP kinase during apoptosis induced by human amy‐

[183] Evans P, Sacan A, Ungar L, Tozeren A. Sequence alignment reveals possible MAPK

[184] Gee K, Angel JB, Mishra S, Blahoianu MA, Kumar A. IL-10 regulation by HIV-Tat in primary human monocytic cells: involvement of calmodulin/calmodulin-dependent protein kinase-activated p38 MAPK and Sp-1 and CREB-1 transcription factors. J Im‐

[185] Saxena M, Busca A, Pandey S, Kryworuchko M, Kumar A. CpG protects human monocytic cells against HIV-Vpr-induced apoptosis by cellular inhibitor of apopto‐ sis-2 through the calcium-activated JNK pathway in a TLR9-independent manner. J

[186] Muthumani K, Choo AY, Shedlock DJ, Laddy DJ, Sundaram SG, Hirao L, et al. Hu‐ man immunodeficiency virus type 1 Nef induces programmed death 1 expression through a p38 mitogen-activated protein kinase-dependent mechanism. J Virol 2008

[187] Alhetheel A. HIV-induced dysregulation of IFN-gamma signaling and programmed

lin in cultured pancreatic beta-cells. FEBS J 2006 Aug;273(16):3779-91.

docking motifs on HIV proteins. PLoS One 2010;5(1):e8942.

cell death in human primary monocytes. Ph D Thesis, 2010.

ylation. Mol Cell Biol 1997 Nov;17(11):6508-16.

Genes Dev 1993 Nov;7(11):2135-48.

30 Current Perspectives in HIV Infection

munol 2007 Jan 15;178(2):798-807.

Immunol 2011 Dec 1;187(11):5865-78.

Dec;82(23):11536-44.

DC are key regulators of immunity in view of the fact that they are involved in immune re‐ sponses against infectious diseases, allergy and cancer [1, 2]. Ralph Steinman was awarded the Nobel Prize for Medicine 2011 for DC discovery in 1973 [3]. Steinman and Cohn [3] de‐ scribed a novel cell type in mouse spleen, which they named ´dendritic cell´ due to their tree-like shape. The major function of DC is the induction of adaptive immunity in the LN.Yet, DC can also interact with innate immune cells, for instance natural killer (NK) and NKT cells [1, 4].

Upon entry of HIV into the host, the virus has to be transported from mucosal surfaces to lymphatic tissues, where it is transmitted to its primary targets, CD4+ T lymphocytes. This process is thought to be contrived by DC.

DC thereby play critical roles during HIV and SIV (simian immunodeficiency virus) infection.

The skin and mucosa are composed of two compartments, the epidermis and the dermis (skin) or stratified squamous epithelium and lamina propria (mucosa), each containing a major subset of DC - Langerhans cells (LC) reside in the suprabasal layers of the epidermis and epithelia [5], while dermal/interstitial DC are distributed throughout the connective tis‐ sue of the dermis [6, 7].

Both subsets represent immature DC that are very efficient in Ag uptake and processing. As immature DC (iDC), they reside in peripheral tissue, which they survey for invading patho‐ gens. Upon encounter with antigen (Ag), DC mature (mDC) and migrate to the draining lymph nodes (LN). They pass through different maturation stages, which enable them to fulfill specific tasks such as the uptake, the processing and the presentation of Ag on major histocompatiblity complex (MHC) molecules to naïve T cells. In the T cell area of lymphatic

tissue the mature DC stimulate Ag-specific CD4+ and CD8+ T cells to proliferate and develop effector function, such as cytokine production and cytotoxic activity. Effector T cells are re‐ cruited to inflamed peripheral tissue and participate in the elimination of pathogens and in‐ fected cells. This very particular life cycle illustrates why DC are called the ´sentinels of the immune system´ [8].

In humans, different DC subsets have been identified in blood, spleen and skin, but little is known respecting resident and migratory DC in human LN. This book chapter will review the major DC subsets found in humans and their role in HIV-pathogenesis. If data are avail‐ able, also the role of the viral opsonization pattern and its impact on DC interaction will be discussed.

### **2. DC subsets and their role in HIV infection**

DC are divided into two main groups: conventional myeloid DC (cDC) and non-convention‐ al plasmacytoid DC (pDC) (Figure 1). As recently described byDoulatov et al. (2010) [9], hu‐ man multi-lymphoid progenitors can bring forth all lymphoid cell types, including monocytes, macrophages and DC. Nonetheless, most DC in steady-state emerge from a common myeloid progenitor [10]. DC areheterogenous subtypes with distinct functions, properties and localization [11]. DC progenitors migrate from the bone-marrow through the blood to lymphoid organs and peripheral tissues. There, they give rise to different cDC sub‐ sets (Figure 1). LC display an exception within the cDC group since they maintain in the epi‐ dermis independent on circulating precursors [12]. Within cDC, migratory and lymphoidresident DC are distinguished: migratory DC travel from peripheral tissues to lymphoid organs, whereas lymphoid-resident DC populate lymphoid organs during their whole lifespan and lack the migratory function. In humans cDC comprise Langerhans Cells (LC), der‐ mal DC (CD103+ and CD103- ), BDCA1+ (CD1c)- and BDCA3+ (CD141) DC, and the recently described CD56+ DC (Figure 1). They are localized in the skin, secondary lymphoid organs (spleen, tonsils) and blood. pDC develop in the bone-marrow and then they reside in lym‐ phoid organs [13]. HLA-DR+ CD123+ pDC express BDCA2 and this cell subset is found in blood, secondary lymphoid organs as well as peripheral tissues, e.g. skin or lungs (Figure 1). The cDC subtypes and pDC express a different receptor repertoir and comprise distinct functions with respect to HIV spread, antiviral activity and transmission, which is reviewed below and shown in Figure 1 (Table adapted from Altfeld et al., [14]). Both cell types are resident in lymphoid tissues in the steady state, but during an inflammatory response, pDC and cDC are actively recruited to these tissues [15-17].

localization in mucosal tissues and their long dendrites to efficiently capture Ag, they comprise the first line defense against mucosal infections. After Ag acquisition, LC start to mature, as represented by up-regulation of co-stimulatory molecules (CD80, CD86, CD40), MHC class I and II molecules, CD83 and CCR7 and down-regulation of Langerin

**Figure 1.** DC-subsets and functions during HIV-infection (Table adapted from *Altfeld et al., 2011*; CD56+ DC added). HIV co-localizes with Langerin in LC to high extend as shown by confocal microscopic analyses (co-localization: yel‐ low). CD1a+ LC were isolated from human skin, incubated with HIV for 2 hrs, fixed and permeabilized with Cytofix/ perm (BD Biosciences). The cells were then stained using an anti-human Langerin-PE mAb (red, Dendritics) and the anti-HIV-Ab KC57-FITC ((green, Beckman Coulter). The nucleus was stained using DRAQ5TM (blue, Invitrogen) (*Posch et*

Role of Dendritic Cell Subsets on HIV-Specific Immunity

http://dx.doi.org/10.5772/52744

33

Due to CCR7 up-regulation, the mature LC migrate to the LN along a CCL19 and CCL21-leu (leucine isoform of CCL21) gradient to efficiently prime T cells there [23]. Beside initiating an effective adaptive immune response, LC were illustrated by DeWitte et al. [24, 25] to also have important functions with respect to innate immune responses. Beside a specific set of TLRs (TLR2, 3, 5) and high expression of CD1a, LC express Langerin and contain Birbeck granules that might be crucial to their innate function [21, 26-29] (Figure 1). The C-type lec‐ tin Langerin interacts with non-opsonized HIV-1 (Figure 2) and other pathogens such as fungi and bacteria, via fucose or mannose residues. Thereby degradation of HIV-1 in Bir‐

beck granules is promoted and HIV-1 dissemination is limited [24].

and E-cadherin [22].

*al., unpublished*).

#### **2.1. cDC**

#### *2.1.1. LC and HIV*

LC survey the basal and suprabasal layers of the stratified squamous epithelium of the skin and oral and ano-genital mucosa for invading pathogens [18-21]. Due to their ideal

#### Role of Dendritic Cell Subsets on HIV-Specific Immunity http://dx.doi.org/10.5772/52744 33

tissue the mature DC stimulate Ag-specific CD4+

**2. DC subsets and their role in HIV infection**

and CD103-

and cDC are actively recruited to these tissues [15-17].

), BDCA1+

CD123+

immune system´ [8].

32 Current Perspectives in HIV Infection

discussed.

mal DC (CD103+

described CD56+

**2.1. cDC**

*2.1.1. LC and HIV*

phoid organs [13]. HLA-DR+

effector function, such as cytokine production and cytotoxic activity. Effector T cells are re‐ cruited to inflamed peripheral tissue and participate in the elimination of pathogens and in‐ fected cells. This very particular life cycle illustrates why DC are called the ´sentinels of the

In humans, different DC subsets have been identified in blood, spleen and skin, but little is known respecting resident and migratory DC in human LN. This book chapter will review the major DC subsets found in humans and their role in HIV-pathogenesis. If data are avail‐ able, also the role of the viral opsonization pattern and its impact on DC interaction will be

DC are divided into two main groups: conventional myeloid DC (cDC) and non-convention‐ al plasmacytoid DC (pDC) (Figure 1). As recently described byDoulatov et al. (2010) [9], hu‐ man multi-lymphoid progenitors can bring forth all lymphoid cell types, including monocytes, macrophages and DC. Nonetheless, most DC in steady-state emerge from a common myeloid progenitor [10]. DC areheterogenous subtypes with distinct functions, properties and localization [11]. DC progenitors migrate from the bone-marrow through the blood to lymphoid organs and peripheral tissues. There, they give rise to different cDC sub‐ sets (Figure 1). LC display an exception within the cDC group since they maintain in the epi‐ dermis independent on circulating precursors [12]. Within cDC, migratory and lymphoidresident DC are distinguished: migratory DC travel from peripheral tissues to lymphoid organs, whereas lymphoid-resident DC populate lymphoid organs during their whole lifespan and lack the migratory function. In humans cDC comprise Langerhans Cells (LC), der‐

(CD1c)- and BDCA3+

(spleen, tonsils) and blood. pDC develop in the bone-marrow and then they reside in lym‐

blood, secondary lymphoid organs as well as peripheral tissues, e.g. skin or lungs (Figure 1). The cDC subtypes and pDC express a different receptor repertoir and comprise distinct functions with respect to HIV spread, antiviral activity and transmission, which is reviewed below and shown in Figure 1 (Table adapted from Altfeld et al., [14]). Both cell types are resident in lymphoid tissues in the steady state, but during an inflammatory response, pDC

LC survey the basal and suprabasal layers of the stratified squamous epithelium of the skin and oral and ano-genital mucosa for invading pathogens [18-21]. Due to their ideal

DC (Figure 1). They are localized in the skin, secondary lymphoid organs

pDC express BDCA2 and this cell subset is found in

and CD8+ T cells to proliferate and develop

(CD141) DC, and the recently

**Figure 1.** DC-subsets and functions during HIV-infection (Table adapted from *Altfeld et al., 2011*; CD56+ DC added). HIV co-localizes with Langerin in LC to high extend as shown by confocal microscopic analyses (co-localization: yel‐ low). CD1a+ LC were isolated from human skin, incubated with HIV for 2 hrs, fixed and permeabilized with Cytofix/ perm (BD Biosciences). The cells were then stained using an anti-human Langerin-PE mAb (red, Dendritics) and the anti-HIV-Ab KC57-FITC ((green, Beckman Coulter). The nucleus was stained using DRAQ5TM (blue, Invitrogen) (*Posch et al., unpublished*).

localization in mucosal tissues and their long dendrites to efficiently capture Ag, they comprise the first line defense against mucosal infections. After Ag acquisition, LC start to mature, as represented by up-regulation of co-stimulatory molecules (CD80, CD86, CD40), MHC class I and II molecules, CD83 and CCR7 and down-regulation of Langerin and E-cadherin [22].

Due to CCR7 up-regulation, the mature LC migrate to the LN along a CCL19 and CCL21-leu (leucine isoform of CCL21) gradient to efficiently prime T cells there [23]. Beside initiating an effective adaptive immune response, LC were illustrated by DeWitte et al. [24, 25] to also have important functions with respect to innate immune responses. Beside a specific set of TLRs (TLR2, 3, 5) and high expression of CD1a, LC express Langerin and contain Birbeck granules that might be crucial to their innate function [21, 26-29] (Figure 1). The C-type lec‐ tin Langerin interacts with non-opsonized HIV-1 (Figure 2) and other pathogens such as fungi and bacteria, via fucose or mannose residues. Thereby degradation of HIV-1 in Bir‐ beck granules is promoted and HIV-1 dissemination is limited [24].

As demonstrated, if the host system is facing other sexually transmitted infections, the anti-HIV-1-barrier of LC is abrogated and HIV-1 transfer to susceptible CD4+ T cells is promoted [20, 36, 37]. Pathogens, such as Candida or Neisseria, directly interact with Langerin and compete with HIV-1-binding. Additional factors explaining the by-passing of the anti-

Role of Dendritic Cell Subsets on HIV-Specific Immunity

http://dx.doi.org/10.5772/52744

35

**•** infections, e.g. Herpes simplex virus infection, down-regulate Langerin surface expres‐

**•** the HIV-1 entry receptors CD4 and CCR5 are up-regulated during additional sexually

**•** or the antiviral function of Langerin is reverted by inflammation-induced TNF-α (tumornecrosis-factor α) production due to Candida albicans or Neisseria gonorrhoea [36].

These observations allow to conclude that during acute co-infection the anti-viral function of

Not only acute co-infection, but also opsonization of HIV with either complement fragments or specific Abs might result in reduction or abolishment of the anti-viral function mediated by Langerin (*Wilflingseder and Posch, unpublished data*). Upon entry of viruses into the body, immediate non-specific immune responses are triggered and within a short time the innate immune system is completely activated. During acute infection multiple humoral and cellu‐ lar players, including cytokines, complement, acute-phase proteins, DC, macrophages, and natural killer (NK) cells, that co-operate to generate an efficient defense against infection, are activated. HIV-1 spontaneously triggers the complement system also in absence of specific Abs by interactions of gp41 with C1q [38-41]. Due to regulators of complement activation (RCAs) in the viral surface, HIV-1 is very efficiently protected against virolysis, which nor‐ mally occurs due to MAC (membrane attack complex) formation and destruction of patho‐ gens or infected cells. The incorporation of RCAs in the viral surface acts as protection mechanism and results in opsonization of HIV-1 with complement C3 fragments at the very initial steps following viral entry. After seroconversion, when HIV-1-specific Abs are estab‐ lished, the virus additionally is opsonized with specific IgGs. The different coating patterns of the virus change the receptor used on DC due to the density of complement fragments or Abs on the viral surface [42]. The C-type lectin-virus interaction becomes rather unimpor‐ tant if the virus is opsonized and is substituted by complement or Fc receptor-virus interac‐ tions as already demonstrated using dermal DC [42]. After LC incubation using complement-opsonized HIV-1, we found that not only sexually transmitted diseases abro‐ gate the antiviral barrier mediated via Langerin but also opsonization of HIV-1 (*Wilflingseder*

In summary, during acute co-infection or by opsonization with complement fragments or Abs, the anti-viral function of LC is significantly reduced due to competition for Langerin or different receptor utilization. This facilitates HIV-1 infection of LC via CD4 and CCR5, intra‐

HIV-1-barrier function of Langerin are that:

transmitted infections [37],

LC is significantly decreased.

*and Posch, unpublished data*).

sion [20],

**•** by high viral loads the receptor becomes saturated,

**Figure 2.** Co-localization of HIV and Langerin on CD1a+ Langerhans Cells isolated from human skin

Early investigations of HIV-LC interactions illustrated that LC are productively infected by HIV and that they efficiently transmit the virus to T cells [30-32]. These results suggested that HIV take advantage of the antigen-capturing properties of LC to reach the T cell zone in the lymphatic tissues and via this route, HIV can establish a productive infection of the host. However, *in vivo* only low percentages of LC are infected and despite abundant expression of the primary HIV-receptor CD4 and the chemokine co-receptor CCR5, high HIV-1 concen‐ trations are required to infect LC *in vitro* [31, 32]. As shown by Wu and KewalRemani [33] the percentages to acquire HIV-1 after heterosexual contact with an HIV-positive individual are between 0.01 to 0.1%, which might be due to a restriction by LC.

Engagement of Langerin trimers on the surface of LC induces formation of Birbeck granules, which are part of the endosomal recycling system and uniquely found in LC (Figure 3, low‐ er right panel) [34]. Upon capture of mycobacterial lipoproteins by Langerin, these were ex‐ posed to CD1a molecules in Birbeck granules [35], which suggests that Birbeck granule formation displays a non-classical antigen processing pathway [20]. Also HIV-1 attaches to Langerin on LC and is subsequently routed to Birbeck granules, which points to a role of the granules with respect to degradation of viruses.

Studies by Gejitenbeek´s laboratory [24] showed that under homeostatic conditions, Lan‐ gerin expressed on LC and acts as restriction factor for HIV infection. They demonstrated that, if HIV-gp120 attaches to Langerin, the viral particle is internalized and subsequently degraded in Birbeck granules. Thus, LC are protected from infection with incoming, nonopsonized HIV particles and HIV-1 is not disseminated throughout the host [24]. The rap‐ id internalization of HIV-1 into LC by Langerin impedes interactions and subsequent fusion with CD4 and CCR5 and also prevents transmission to the main target cells of the virus, CD4+ T cells. Thereby, Langerin acts as a protective anti-HIV barrier during the first steps of HIV-1 infection, if the virus is non-opsonized and if sexually transmitted pathogens are lacking.

As demonstrated, if the host system is facing other sexually transmitted infections, the anti-HIV-1-barrier of LC is abrogated and HIV-1 transfer to susceptible CD4+ T cells is promoted [20, 36, 37]. Pathogens, such as Candida or Neisseria, directly interact with Langerin and compete with HIV-1-binding. Additional factors explaining the by-passing of the anti-HIV-1-barrier function of Langerin are that:

**•** by high viral loads the receptor becomes saturated,

**Figure 2.** Co-localization of HIV and Langerin on CD1a+ Langerhans Cells isolated from human skin

are between 0.01 to 0.1%, which might be due to a restriction by LC.

granules with respect to degradation of viruses.

pathogens are lacking.

34 Current Perspectives in HIV Infection

Early investigations of HIV-LC interactions illustrated that LC are productively infected by HIV and that they efficiently transmit the virus to T cells [30-32]. These results suggested that HIV take advantage of the antigen-capturing properties of LC to reach the T cell zone in the lymphatic tissues and via this route, HIV can establish a productive infection of the host. However, *in vivo* only low percentages of LC are infected and despite abundant expression of the primary HIV-receptor CD4 and the chemokine co-receptor CCR5, high HIV-1 concen‐ trations are required to infect LC *in vitro* [31, 32]. As shown by Wu and KewalRemani [33] the percentages to acquire HIV-1 after heterosexual contact with an HIV-positive individual

Engagement of Langerin trimers on the surface of LC induces formation of Birbeck granules, which are part of the endosomal recycling system and uniquely found in LC (Figure 3, low‐ er right panel) [34]. Upon capture of mycobacterial lipoproteins by Langerin, these were ex‐ posed to CD1a molecules in Birbeck granules [35], which suggests that Birbeck granule formation displays a non-classical antigen processing pathway [20]. Also HIV-1 attaches to Langerin on LC and is subsequently routed to Birbeck granules, which points to a role of the

Studies by Gejitenbeek´s laboratory [24] showed that under homeostatic conditions, Lan‐ gerin expressed on LC and acts as restriction factor for HIV infection. They demonstrated that, if HIV-gp120 attaches to Langerin, the viral particle is internalized and subsequently degraded in Birbeck granules. Thus, LC are protected from infection with incoming, nonopsonized HIV particles and HIV-1 is not disseminated throughout the host [24]. The rap‐ id internalization of HIV-1 into LC by Langerin impedes interactions and subsequent fusion with CD4 and CCR5 and also prevents transmission to the main target cells of the virus, CD4+ T cells. Thereby, Langerin acts as a protective anti-HIV barrier during the first steps of HIV-1 infection, if the virus is non-opsonized and if sexually transmitted


These observations allow to conclude that during acute co-infection the anti-viral function of LC is significantly decreased.

Not only acute co-infection, but also opsonization of HIV with either complement fragments or specific Abs might result in reduction or abolishment of the anti-viral function mediated by Langerin (*Wilflingseder and Posch, unpublished data*). Upon entry of viruses into the body, immediate non-specific immune responses are triggered and within a short time the innate immune system is completely activated. During acute infection multiple humoral and cellu‐ lar players, including cytokines, complement, acute-phase proteins, DC, macrophages, and natural killer (NK) cells, that co-operate to generate an efficient defense against infection, are activated. HIV-1 spontaneously triggers the complement system also in absence of specific Abs by interactions of gp41 with C1q [38-41]. Due to regulators of complement activation (RCAs) in the viral surface, HIV-1 is very efficiently protected against virolysis, which nor‐ mally occurs due to MAC (membrane attack complex) formation and destruction of patho‐ gens or infected cells. The incorporation of RCAs in the viral surface acts as protection mechanism and results in opsonization of HIV-1 with complement C3 fragments at the very initial steps following viral entry. After seroconversion, when HIV-1-specific Abs are estab‐ lished, the virus additionally is opsonized with specific IgGs. The different coating patterns of the virus change the receptor used on DC due to the density of complement fragments or Abs on the viral surface [42]. The C-type lectin-virus interaction becomes rather unimpor‐ tant if the virus is opsonized and is substituted by complement or Fc receptor-virus interac‐ tions as already demonstrated using dermal DC [42]. After LC incubation using complement-opsonized HIV-1, we found that not only sexually transmitted diseases abro‐ gate the antiviral barrier mediated via Langerin but also opsonization of HIV-1 (*Wilflingseder and Posch, unpublished data*).

In summary, during acute co-infection or by opsonization with complement fragments or Abs, the anti-viral function of LC is significantly reduced due to competition for Langerin or different receptor utilization. This facilitates HIV-1 infection of LC via CD4 and CCR5, intra‐ cellular uptake of the virus (Figure 3) and promotion of HIV-1 transfer to its targets, CD4+ T cells.

amounts of virions in large vesicular compartments deeper within DC [55]. This points to a

Role of Dendritic Cell Subsets on HIV-Specific Immunity

http://dx.doi.org/10.5772/52744

37

**Figure 3.** Uptake of HIV into dendritic cells from human skin. Dendritic cells emigrated from whole skin explants were incubated with HIV for 2h and then fixed and embedded for transmission electron microscopy. Variable amounts of viral particles are taken up by dermal dendritic cells (left panels) and epidermal Langerhans cells (right panels). Lower panels show higher magnifications of membrane-enclosed virus particles in a dermal dendritic cell (left panel; some viruses marked with red/black). In a Langerhans cell (lower right panel) viruses can be seen docking onto the surface membrane (right asterisk) and already taken up into vesicular structures (left asterisk). A Birbeck granule is depicted in the inset as the identifying structure for Langerhans cells. N, nucleus.(Photos courtesy of Hella Stössel and Nikolaus

Romani).

diverse entry and handling of virions within iDC and mDC.

On the other hand LC were implicated in establishment of infection due to their location in the foreskin and due to compelling evidence that male circumcision efficiently reduces the risk to become infected with HIV-1 [43]. It was furthermore shown *in vivo* in highly HIV-1 exposed but (IgG) seronegative individuals, that gp41-specific IgA Abs efficiently blocked transfer of sexually transmitted HIV-1 [44-46]. A very recent study by Tudor et al. [46] illus‐ trated that monomeric 2F5 IgA2 bound to gp41 MPER (membrane proximal external region) and free virus with greater efficiency than IgG1 and interferred with the initial HIV-1 trans‐ mission via Langerhans Cells. 2F5 IgA2 and IgG1 monomers blocked HIV-1 transcytosis in monostratified or multilayered epithelia as well as in rectal tissue [46, 47]. These Abs de‐ creased infection of CD4+ T cells and transfer from LC to autologous CD4+ T cells [46]. The 2F5 IgA2 monomer inhibited virus transcytosis and CD4+ T cell infection more efficiently, while the 2F5 IgG1 monomer was superior in blocking the LC-CD4+ T cell transmission. A synergistic effect of both, 2F5 IgA2 and IgG1, was observed with respect to LC-CD4+ T cell transmission and decrease of CD4+ T cell infection [46].

### *2.1.2. Dermal DC and HIV*

Along with LC, HIV-1 firstly attaches to dermal (interstitial) DC upon entry at mucosal sur‐ faces (Figure 1). Dermal DC are underlying the epithelium, do not contain Birbeck granules and express heterogenous amounts of CD1a [48].

Interstitial DC are localized in the dermis and oral, vaginal and colonic lamina propria [6, 49-52]. They are characterized by the expression of CD11c, high expression of various Ctype lectin receptors (Langerin on CD103+ DC, DC-SIGN on CD103- DC, DEC-205 on both subsets), TLR2, 3, 4 and 5 and they secrete various cytokines upon pathogenic stimulation (Figure 1). Since there are only 2 studies available on human CD103+ DC and SIV [53, 54], the following chapter refers to CD103- , DC-SIGN+ dermal DC.

*In vitro* experiments showed that DC efficiently capture HIV-1 or SIV, independent on the maturation status of the cells (Figure 3 and [55]) and subsequently transfer the virus to CD4+ T cells, which initiates a vigorous infection [41, 42, 56, 57]. These experiments imply that *in vivo* HIV exploits DC at mucosal sites as shuttles to CD4+ T cells in the LN, but the exact events with respect to virus spread from mucosal sites to LN have not been enlightened yet. Thereby, DC seem to play a significant role in the spread of infection as well as in the induc‐ tion of antiviral immunity.

As shown in Figure 3, dermal DC (left panel) and LC (right panel), which emigrated from whole skin explants, take up variable amounts of HIV-1 particles. As demonstrated by Frank et al. [55], human and macaque DC interacted similarly with SIV and ample amounts of virus were captured by DC. Transmission electron microscopic analyses revealed that iDC, which are endocytically highly active, captured few viral particles near the periphery of the membrane, while mDC, which down-regulate the endocytic capacity, retained high amounts of virions in large vesicular compartments deeper within DC [55]. This points to a diverse entry and handling of virions within iDC and mDC.

cellular uptake of the virus (Figure 3) and promotion of HIV-1 transfer to its targets, CD4+

On the other hand LC were implicated in establishment of infection due to their location in the foreskin and due to compelling evidence that male circumcision efficiently reduces the risk to become infected with HIV-1 [43]. It was furthermore shown *in vivo* in highly HIV-1 exposed but (IgG) seronegative individuals, that gp41-specific IgA Abs efficiently blocked transfer of sexually transmitted HIV-1 [44-46]. A very recent study by Tudor et al. [46] illus‐ trated that monomeric 2F5 IgA2 bound to gp41 MPER (membrane proximal external region) and free virus with greater efficiency than IgG1 and interferred with the initial HIV-1 trans‐ mission via Langerhans Cells. 2F5 IgA2 and IgG1 monomers blocked HIV-1 transcytosis in monostratified or multilayered epithelia as well as in rectal tissue [46, 47]. These Abs de‐

while the 2F5 IgG1 monomer was superior in blocking the LC-CD4+ T cell transmission. A synergistic effect of both, 2F5 IgA2 and IgG1, was observed with respect to LC-CD4+

Along with LC, HIV-1 firstly attaches to dermal (interstitial) DC upon entry at mucosal sur‐ faces (Figure 1). Dermal DC are underlying the epithelium, do not contain Birbeck granules

Interstitial DC are localized in the dermis and oral, vaginal and colonic lamina propria [6, 49-52]. They are characterized by the expression of CD11c, high expression of various C-

subsets), TLR2, 3, 4 and 5 and they secrete various cytokines upon pathogenic stimulation (Figure 1). Since there are only 2 studies available on human CD103+ DC and SIV [53, 54],

*In vitro* experiments showed that DC efficiently capture HIV-1 or SIV, independent on the maturation status of the cells (Figure 3 and [55]) and subsequently transfer the virus to CD4+ T cells, which initiates a vigorous infection [41, 42, 56, 57]. These experiments imply that *in*

events with respect to virus spread from mucosal sites to LN have not been enlightened yet. Thereby, DC seem to play a significant role in the spread of infection as well as in the induc‐

As shown in Figure 3, dermal DC (left panel) and LC (right panel), which emigrated from whole skin explants, take up variable amounts of HIV-1 particles. As demonstrated by Frank et al. [55], human and macaque DC interacted similarly with SIV and ample amounts of virus were captured by DC. Transmission electron microscopic analyses revealed that iDC, which are endocytically highly active, captured few viral particles near the periphery of the membrane, while mDC, which down-regulate the endocytic capacity, retained high

, DC-SIGN+

DC, DC-SIGN on CD103-

dermal DC.

T cell infection [46].

T cells and transfer from LC to autologous CD4+ T cells [46]. The

T cell infection more efficiently,

DC, DEC-205 on both

T cells in the LN, but the exact

cells.

creased infection of CD4+

36 Current Perspectives in HIV Infection

*2.1.2. Dermal DC and HIV*

transmission and decrease of CD4+

2F5 IgA2 monomer inhibited virus transcytosis and CD4+

and express heterogenous amounts of CD1a [48].

*vivo* HIV exploits DC at mucosal sites as shuttles to CD4+

type lectin receptors (Langerin on CD103+

the following chapter refers to CD103-

tion of antiviral immunity.

T

T cell

**Figure 3.** Uptake of HIV into dendritic cells from human skin. Dendritic cells emigrated from whole skin explants were incubated with HIV for 2h and then fixed and embedded for transmission electron microscopy. Variable amounts of viral particles are taken up by dermal dendritic cells (left panels) and epidermal Langerhans cells (right panels). Lower panels show higher magnifications of membrane-enclosed virus particles in a dermal dendritic cell (left panel; some viruses marked with red/black). In a Langerhans cell (lower right panel) viruses can be seen docking onto the surface membrane (right asterisk) and already taken up into vesicular structures (left asterisk). A Birbeck granule is depicted in the inset as the identifying structure for Langerhans cells. N, nucleus.(Photos courtesy of Hella Stössel and Nikolaus Romani).

Beside the different handling of HIV-1 or SIV within iDC and mDC, opsonization of the vi‐ rus with either complement fragments and/or Abs significantly affects the binding mecha‐ nism, internalization and infection of DC as well as their T cell stimulatory capacity [41, 42, 58]. As shown by Pruenster et al. [42], the complement cloud around the virus significantly blocked the accessibility of gp120 and therefore interfered with C-type lectin interaction.

of DC [62, 63]. Thereby, DC-SIGN efficiently transfers HIV-1 to CD4+ T cells, enhances infec‐

**Figure 4.** Binding of differentially opsonized HIV (non-opsonized HIV, HIV-C, HIV-Ig) in absence and presence of a blocking anti-human DC-SIGN, CR3 [CD11b] (TMG6.5) or CD32 (AT-10) antibodies. Binding of non-opsonized HIV was signficantly decreased in the presence of a blocking anti-DC-SIGN Ab, but not affected by pre-incubation of the cells with a blocking anti-CR3- or CD32-Ab (white bars). HIV-C-interaction with DC was inhibited using a blocking anti-CD11b (CR3)-Ab TMG6.5, but not by anti-DC-SIGN or CD32 (grey bars). Binding of IgG-opsonized HIV was inhibited by

Lastly, the antigen-presenting capacity of DC was also shown to be modulated by the opso‐ nization pattern of the virus [58]. Earlier studies illustrated the role of complement opsoni‐ zation respecting induction of effective CTL responses against viral infections, but the exact mechanism was not determined [64-66]. The exclusive role of DC in priming naïve CD8+

cells in response to exogenous cell-associated as well as endogenously synthesized Ags has been shown [67, 68]. Endogenously synthesized antigens from DC infected with LCMV (choriomeningitis virus) mediated strong CTL responses, while macrophages and B cells in‐

We recently found that opsonization of retroviral particles with complement fragments enhanced the ability of DC to induce CTL responses both *in vitro* and *in vivo* [58]. HIV-Cloaded DC mediated significantly higher CD8+ T cell expansion and signficantly better an‐ tiviral activity than DC exposed to non-opsonized HIV *in vitro*. This was further verified

T

using a blocking anti-human CD32, but not DC-SIGN or CD11b-Ab (black bars).

fected with LCMV did not induce CTLs [68].

T cell co-cultures and facilitates '*trans*'-infection of the T cells [62].

Role of Dendritic Cell Subsets on HIV-Specific Immunity

http://dx.doi.org/10.5772/52744

39

tion in DC-CD4+

Similar amounts of HIV-1 bound to the surface of DC independent on the opsonization pat‐ tern of the virus (Pruenster et al., 2005). The attachment of the differentially opsonized HIV-1-preparations was found to be specific (Figure 4 [*Wilflingseder and Posch, unpublished data*]), since pre-incubation of the DC with blocking Abs against human DC-SIGN, CD11b (CR3-α chain) or CD32 (FcγRII) particularly blocked the interactions with the corresponding virus preparations:


Additionally, we found variations respecting infection of DC with differentially opsonized HIV-1 preparations [41]. Productive infection of DC and LC with HIV-1 was described to be relatively inefficient compared to HIV-infection of CD4+ T cells and HIV- or SIV-infected DC are rarely detected *in vivo* (rev. in Piguet and Steinman[59]). Our study using non-, comple‐ ment-, complement-Ig- or Ig-opsonized HIV-1 uncovered that complement-opsonization of HIV-1 significantly enhanced DC-infection compared to non-opsonized HIV [41] and further‐ more acted as an endogenous adjuvans for DC-mediated induction of HIV-specific CTLs [58].

In contrast, HIV-1 coated with specific, non-neutralizing Abs significantly impaired infec‐ tion of and integration in DC and also ´*trans*´-infection of CD4+ T cells after delayed addition of T cells [41].

Despite the low-level productive infection of DC, non-opsonized HIV-1 is very efficiently transmitted to T cells either via de novo (´*cis*´-transfer) or without (´*trans*´-)infection [60]. This is also true for Ab-opsonized HIV-1, if CD4+ T cells are added immediately to HIV-ex‐ posed DC [41]. Especially C-type lectins, such as DC-SIGN on dermal DC, were connected to transmitting HIV-1 to T cells in the LN [60, 61]. Similar to Langerin, DC-SIGN has high affinity for mannose and fucose structures, but despite sharing this feature these receptors exert completely different effects and functions regarding pathogen processing. Dermal CD103- DC express DC-SIGN, which captures low titres of HIV-1 by interaction with the en‐ velope glycoprotein gp120 [62]. By complexing DC-SIGN via gp120, HIV-1 is protected from degradation within the DC in contrast to Langerin, which promotes degradation of the virus through Birbeck granules as described above [24, 62]. DC-SIGN-complexed HIV-1 remains stable and infectious over prolonged periods of time within non-lysosomal acidic organelles

of DC [62, 63]. Thereby, DC-SIGN efficiently transfers HIV-1 to CD4+ T cells, enhances infec‐ tion in DC-CD4+ T cell co-cultures and facilitates '*trans*'-infection of the T cells [62].

Beside the different handling of HIV-1 or SIV within iDC and mDC, opsonization of the vi‐ rus with either complement fragments and/or Abs significantly affects the binding mecha‐ nism, internalization and infection of DC as well as their T cell stimulatory capacity [41, 42, 58]. As shown by Pruenster et al. [42], the complement cloud around the virus significantly blocked the accessibility of gp120 and therefore interfered with C-type lectin interaction.

Similar amounts of HIV-1 bound to the surface of DC independent on the opsonization pat‐ tern of the virus (Pruenster et al., 2005). The attachment of the differentially opsonized HIV-1-preparations was found to be specific (Figure 4 [*Wilflingseder and Posch, unpublished data*]), since pre-incubation of the DC with blocking Abs against human DC-SIGN, CD11b (CR3-α chain) or CD32 (FcγRII) particularly blocked the interactions with the corresponding

**•** blocking α-DC-SIGN mAb inhibited interaction with non-opsonized HIV-1 (Figure 4,

**•** blocking α-CR3mAb (TMG6.5) significantly interferred with binding of complement-

**•** blocking α-CD32mAb (AT10) inhibited binding of Ab-opsonized HIV-1 (Figure 4, HIV-

Additionally, we found variations respecting infection of DC with differentially opsonized HIV-1 preparations [41]. Productive infection of DC and LC with HIV-1 was described to be

are rarely detected *in vivo* (rev. in Piguet and Steinman[59]). Our study using non-, comple‐ ment-, complement-Ig- or Ig-opsonized HIV-1 uncovered that complement-opsonization of HIV-1 significantly enhanced DC-infection compared to non-opsonized HIV [41] and further‐ more acted as an endogenous adjuvans for DC-mediated induction of HIV-specific CTLs [58].

In contrast, HIV-1 coated with specific, non-neutralizing Abs significantly impaired infec‐ tion of and integration in DC and also ´*trans*´-infection of CD4+ T cells after delayed addition

Despite the low-level productive infection of DC, non-opsonized HIV-1 is very efficiently transmitted to T cells either via de novo (´*cis*´-transfer) or without (´*trans*´-)infection [60].

posed DC [41]. Especially C-type lectins, such as DC-SIGN on dermal DC, were connected to transmitting HIV-1 to T cells in the LN [60, 61]. Similar to Langerin, DC-SIGN has high affinity for mannose and fucose structures, but despite sharing this feature these receptors exert completely different effects and functions regarding pathogen processing. Dermal CD103- DC express DC-SIGN, which captures low titres of HIV-1 by interaction with the en‐ velope glycoprotein gp120 [62]. By complexing DC-SIGN via gp120, HIV-1 is protected from degradation within the DC in contrast to Langerin, which promotes degradation of the virus through Birbeck granules as described above [24, 62]. DC-SIGN-complexed HIV-1 remains stable and infectious over prolonged periods of time within non-lysosomal acidic organelles

T cells and HIV- or SIV-infected DC

T cells are added immediately to HIV-ex‐

opsonized HIV (HIV-C) to DC (Fig.4, HIV-C) and

relatively inefficient compared to HIV-infection of CD4+

This is also true for Ab-opsonized HIV-1, if CD4+

virus preparations:

38 Current Perspectives in HIV Infection

HIV),

Ig).

of T cells [41].

**Figure 4.** Binding of differentially opsonized HIV (non-opsonized HIV, HIV-C, HIV-Ig) in absence and presence of a blocking anti-human DC-SIGN, CR3 [CD11b] (TMG6.5) or CD32 (AT-10) antibodies. Binding of non-opsonized HIV was signficantly decreased in the presence of a blocking anti-DC-SIGN Ab, but not affected by pre-incubation of the cells with a blocking anti-CR3- or CD32-Ab (white bars). HIV-C-interaction with DC was inhibited using a blocking anti-CD11b (CR3)-Ab TMG6.5, but not by anti-DC-SIGN or CD32 (grey bars). Binding of IgG-opsonized HIV was inhibited by using a blocking anti-human CD32, but not DC-SIGN or CD11b-Ab (black bars).

Lastly, the antigen-presenting capacity of DC was also shown to be modulated by the opso‐ nization pattern of the virus [58]. Earlier studies illustrated the role of complement opsoni‐ zation respecting induction of effective CTL responses against viral infections, but the exact mechanism was not determined [64-66]. The exclusive role of DC in priming naïve CD8+ T cells in response to exogenous cell-associated as well as endogenously synthesized Ags has been shown [67, 68]. Endogenously synthesized antigens from DC infected with LCMV (choriomeningitis virus) mediated strong CTL responses, while macrophages and B cells in‐ fected with LCMV did not induce CTLs [68].

We recently found that opsonization of retroviral particles with complement fragments enhanced the ability of DC to induce CTL responses both *in vitro* and *in vivo* [58]. HIV-Cloaded DC mediated significantly higher CD8+ T cell expansion and signficantly better an‐ tiviral activity than DC exposed to non-opsonized HIV *in vitro*. This was further verified

*in vivo* using the murine Friend virus model. These results indicated that ´complement acts as natural adjuvant for DC-induced expansion and differentiation of specific CTLs against retroviruses´ [58].

tion: ´de novo´ HIV-1-infection of DC before transfer to T cells) was also observable in

by the virus, were not able to promote long-term transfer of HIV-1 to susceptible T cells [41].

producers of IFN-λ in response to dsRNA poly I:C [80].As recently described by Dutertre et

counts were reduced in 15 viremic, untreated patients compared to 8 HIV-1-positive indi‐ viduals under treatment and 13 healthy donors. By using this method, they illustrated that

shown to be more significantly down-modulated in viremic patients compared to controls [82] and it remains to be investigated by longitudinal studies, if combined antiretroviral

cultivation they acquire DC-like morphology with increased levels of above mentioned sur‐

results in secretion of IFNγ, TNF-α, and IL-1β [84]. The role of CD56+ DC respecting HIV-1

Plasmacytoid DC (pDC) (Figure 1) or type 1 IFN-producing dendritic cells are innate im‐ mune cells in blood, which are specialized in releasing massive amounts of IFNα and IFNβ upon viral challenge, including HIV-1 [83]. They constitute <0.2-0.5% of peripheral blood mononuclear cells (PBMC) [85] and in humans, pDC express the characteristic surface mark‐ ers BDCA-2 (CD303, CLEC4C) and CD123 along with BDCA4 (CD304, NRP1), but they do

pDCs are key players of the innate immune response *in vivo* and they can prime adaptive immunity due to the afore mentioned production of high type I interferon levels, especially upon exposure to viral products [15, 83]. Upon stimulation with DNA or RNA viruses, they produce up to 1000-fold higher amounts of type I interferons than other cells [84, 87, 88]. The IFNα production in pDC by viruses represents a two-step process – uptake of viruses occurs due to recognition of envelope glycoproteins by C-type lectin receptors, e.g. mannose receptor or BDCA2, but induction of IFNα in fact starts in endosomal compartments by liga‐ tion of TLR9 or TLR7 [89-91]. Pathogenic single-stranded RNA or unmethylated DNA are mainly recognized by TLR7 and TLR9 expressed inside pDC [92]. Thus, the viruses have to be ingested by pDC into endosomes and NFkB- and MAPK signals through MyD88 must be stimulated [93]. Not only viruses, but also virus-infected cells can potently activate IFNα production from pDC [94]. Once activated, pDCs mature and produce large quantities of pro-inflammatory and antiviral cytokines [95-97]. pDC respond with high amounts of differ‐

DC represent the human equivalent to mouse CD8α<sup>+</sup>

al. [81] using an 11-color flow cytometric strategy, circulating BDCA1+

therapy can restore the pool of circulating myeloid BDCA1+

infection and pathogenesis needs to be further investigated.

not express CD11c, a marker of myeloid DC, or CD14 [86].

mediate-sized lymphocytes with an HLA-DRhigh, CD80+

both blood DC subsets expressed characteristic lineage markers: BDCA1+

face markers. Upon stimulation, they are able to efficiently stimulate CD56+

fection of DC, efficiently infected autologous CD4+

CD14, while particularly BDCA3+

DC, because non- and complement-opsonized HIV-1, which cause productive in‐

DC exposed to IgG-opsonized HIV-1, which were not productively infected

DC displayed CD56 on their surface. BDCA3+

DC were recently described by Gruenbacher et al. [83] and comprise inter‐

and BDCA3+

T cells in short- and long-term co-cul‐

Role of Dendritic Cell Subsets on HIV-Specific Immunity

DC and they are the major

http://dx.doi.org/10.5772/52744

41

DC.

and CD86+ expression profile. Upon

DC and BDCA3+ DC

DC expressed

γδ T cells, which

DC were

BDCA1+

BDCA3+

tures. BDCA1+

Blood CD56+

**2.2. pDC and HIV**

Additionally, we demonstrated that in contrast to complement opsonization, antibody-coat‐ ing of the viral surface attenuated the CTL-stimulatory capacity of HIV-exposed DC [69]. In some HIV-1-positive individuals, high levels of antibodies and low levels of complement fragments coat the HIV-1 surface and therefore we investigated the effects of the non-neu‐ tralizing Abs bound to the surface of HIV-1 on the CTL-stimulatory capacity of DC. We ob‐ served *ex vivo* and *in vitro* that DC loaded with IgG-opsonized HIV significantly impaired the HIV-1-specific CD8+ T cell response compared to the earlier described efficient CD8+ T cell activation induced by DC exposed to complement-opsonized HIV. These novel modula‐ tory effects of the HIV-1-opsonization pattern on the CTL-activating capacity of DC might influence future vaccination strategies, since strong transient Ab responses subsequent to vaccination might weaken the CTL-induction by DC, which has to be considered [69].

Preferential expression of CCR5 on immature LC and DC restricts the transmission of X4 tropic isolates at the site of infection. Additionally, *ex vivo* analyses revealed that X4-tropic HIV replicate worse in DC and LC compared to R5-tropic viruses [31, 70, 71]. The relatively low susceptibility of DC to HIV-1-infection but efficient transfer of virus to CD4+ T cells was lately ascribed to an HIV-1 escape mechanism from innate recognition by DC [72, 73]. Manel et al. [72] showed that if DC by-pass resistance to HIV-1 infection [74, 75], they mature, exert a type I IFN response as well as adaptive immune responses. More recently, Laguette et al. [73] described the restriction factor SAMHD1 (SAM domain and HD domain-containing protein 1) to be responsible for inhibiting HIV-1 replication in DC and other cells of the mye‐ loid lineage by degrading or preventing accumulation of HIV-1 DNA due to a putative nu‐ cleotidase activity. As shown by Lahouassa et al. [76], SAMHD1 depletes the pool of intracellular dNTPs and thus restricts HIV-1 infection in DC by blocking reverse transcrip‐ tion. These recent important findings respecting a formerly unknown cryptic innate sensor in DC, SAMHD1, and the induction of an efficient type I IFN and adaptive immune re‐ sponse due to DC infection might pave the way for novel therapeutical approaches to treat retroviral infections.

### *2.1.3. Blood DC and HIV*

#### *2.1.3.1. BDCA1+ DC, BDCA3+ DC, CD56+ DC and HIV*

BDCA1+ myeloid DC can be directly isolated from human blood. This population was de‐ scribed to be reduced in the blood of HIV-infected individuals [76-78]. We found that BDCA1+ DC exerted a decreased transmission of HIV-1 to autologous CD4+ T cells, when the virus was opsonized with specific IgGs in contrast to non- or complement-opsonized HIV-1 and when the T cells were added delayed [41]. When CD4+ T cells were immediately added after washing the differentially loaded DC, the same infection efficiency was observed using HIV, HIV-C or HIV-Ig [41]. The two-phase transfer of HIV to DC as described above (*trans*infection: by-passing of the virus from endolysosomal compartments, first 24 hrs; *cis*-infec‐ tion: ´de novo´ HIV-1-infection of DC before transfer to T cells) was also observable in BDCA1+ DC, because non- and complement-opsonized HIV-1, which cause productive in‐ fection of DC, efficiently infected autologous CD4+ T cells in short- and long-term co-cul‐ tures. BDCA1+ DC exposed to IgG-opsonized HIV-1, which were not productively infected by the virus, were not able to promote long-term transfer of HIV-1 to susceptible T cells [41].

BDCA3+ DC represent the human equivalent to mouse CD8α<sup>+</sup> DC and they are the major producers of IFN-λ in response to dsRNA poly I:C [80].As recently described by Dutertre et al. [81] using an 11-color flow cytometric strategy, circulating BDCA1+ DC and BDCA3+ DC counts were reduced in 15 viremic, untreated patients compared to 8 HIV-1-positive indi‐ viduals under treatment and 13 healthy donors. By using this method, they illustrated that both blood DC subsets expressed characteristic lineage markers: BDCA1+ DC expressed CD14, while particularly BDCA3+ DC displayed CD56 on their surface. BDCA3+ DC were shown to be more significantly down-modulated in viremic patients compared to controls [82] and it remains to be investigated by longitudinal studies, if combined antiretroviral therapy can restore the pool of circulating myeloid BDCA1+ and BDCA3+ DC.

Blood CD56+ DC were recently described by Gruenbacher et al. [83] and comprise inter‐ mediate-sized lymphocytes with an HLA-DRhigh, CD80+ and CD86+ expression profile. Upon cultivation they acquire DC-like morphology with increased levels of above mentioned sur‐ face markers. Upon stimulation, they are able to efficiently stimulate CD56+ γδ T cells, which results in secretion of IFNγ, TNF-α, and IL-1β [84]. The role of CD56+ DC respecting HIV-1 infection and pathogenesis needs to be further investigated.

### **2.2. pDC and HIV**

*in vivo* using the murine Friend virus model. These results indicated that ´complement acts as natural adjuvant for DC-induced expansion and differentiation of specific CTLs

Additionally, we demonstrated that in contrast to complement opsonization, antibody-coat‐ ing of the viral surface attenuated the CTL-stimulatory capacity of HIV-exposed DC [69]. In some HIV-1-positive individuals, high levels of antibodies and low levels of complement fragments coat the HIV-1 surface and therefore we investigated the effects of the non-neu‐ tralizing Abs bound to the surface of HIV-1 on the CTL-stimulatory capacity of DC. We ob‐ served *ex vivo* and *in vitro* that DC loaded with IgG-opsonized HIV significantly impaired

cell activation induced by DC exposed to complement-opsonized HIV. These novel modula‐ tory effects of the HIV-1-opsonization pattern on the CTL-activating capacity of DC might influence future vaccination strategies, since strong transient Ab responses subsequent to vaccination might weaken the CTL-induction by DC, which has to be considered [69].

Preferential expression of CCR5 on immature LC and DC restricts the transmission of X4 tropic isolates at the site of infection. Additionally, *ex vivo* analyses revealed that X4-tropic HIV replicate worse in DC and LC compared to R5-tropic viruses [31, 70, 71]. The relatively low susceptibility of DC to HIV-1-infection but efficient transfer of virus to CD4+ T cells was lately ascribed to an HIV-1 escape mechanism from innate recognition by DC [72, 73]. Manel et al. [72] showed that if DC by-pass resistance to HIV-1 infection [74, 75], they mature, exert a type I IFN response as well as adaptive immune responses. More recently, Laguette et al. [73] described the restriction factor SAMHD1 (SAM domain and HD domain-containing protein 1) to be responsible for inhibiting HIV-1 replication in DC and other cells of the mye‐ loid lineage by degrading or preventing accumulation of HIV-1 DNA due to a putative nu‐ cleotidase activity. As shown by Lahouassa et al. [76], SAMHD1 depletes the pool of intracellular dNTPs and thus restricts HIV-1 infection in DC by blocking reverse transcrip‐ tion. These recent important findings respecting a formerly unknown cryptic innate sensor in DC, SAMHD1, and the induction of an efficient type I IFN and adaptive immune re‐ sponse due to DC infection might pave the way for novel therapeutical approaches to treat

T cell response compared to the earlier described efficient CD8+ T

against retroviruses´ [58].

40 Current Perspectives in HIV Infection

the HIV-1-specific CD8+

retroviral infections.

*2.1.3.1. BDCA1+*

BDCA1+

*2.1.3. Blood DC and HIV*

 *DC, BDCA3+*

 *DC, CD56+*

and when the T cells were added delayed [41]. When CD4+

BDCA1+ DC exerted a decreased transmission of HIV-1 to autologous CD4+

 *DC and HIV*

scribed to be reduced in the blood of HIV-infected individuals [76-78]. We found that

virus was opsonized with specific IgGs in contrast to non- or complement-opsonized HIV-1

after washing the differentially loaded DC, the same infection efficiency was observed using HIV, HIV-C or HIV-Ig [41]. The two-phase transfer of HIV to DC as described above (*trans*infection: by-passing of the virus from endolysosomal compartments, first 24 hrs; *cis*-infec‐

myeloid DC can be directly isolated from human blood. This population was de‐

T cells, when the

T cells were immediately added

Plasmacytoid DC (pDC) (Figure 1) or type 1 IFN-producing dendritic cells are innate im‐ mune cells in blood, which are specialized in releasing massive amounts of IFNα and IFNβ upon viral challenge, including HIV-1 [83]. They constitute <0.2-0.5% of peripheral blood mononuclear cells (PBMC) [85] and in humans, pDC express the characteristic surface mark‐ ers BDCA-2 (CD303, CLEC4C) and CD123 along with BDCA4 (CD304, NRP1), but they do not express CD11c, a marker of myeloid DC, or CD14 [86].

pDCs are key players of the innate immune response *in vivo* and they can prime adaptive immunity due to the afore mentioned production of high type I interferon levels, especially upon exposure to viral products [15, 83]. Upon stimulation with DNA or RNA viruses, they produce up to 1000-fold higher amounts of type I interferons than other cells [84, 87, 88]. The IFNα production in pDC by viruses represents a two-step process – uptake of viruses occurs due to recognition of envelope glycoproteins by C-type lectin receptors, e.g. mannose receptor or BDCA2, but induction of IFNα in fact starts in endosomal compartments by liga‐ tion of TLR9 or TLR7 [89-91]. Pathogenic single-stranded RNA or unmethylated DNA are mainly recognized by TLR7 and TLR9 expressed inside pDC [92]. Thus, the viruses have to be ingested by pDC into endosomes and NFkB- and MAPK signals through MyD88 must be stimulated [93]. Not only viruses, but also virus-infected cells can potently activate IFNα production from pDC [94]. Once activated, pDCs mature and produce large quantities of pro-inflammatory and antiviral cytokines [95-97]. pDC respond with high amounts of differ‐ ent IFNα subsets, IFNβ, IFNκ, IFNλ and IFNω on a wide range of enveloped viruses includ‐ ing HIV-1. They additionally produce pro-inflammatory cytokines TNFα, IFNγ and IL-6 as well as chemokines CXCL-10, CCL-5 and CCL-4 among others [98]. Thereby, pDC also act as a linker between innate and adaptive immunity.

animals, thus suggesting that inflamed LN lure cDC away from the sites of infection early during progressive SIV infection [117]. A similar mechanism can be imagined for pDC, which are recruited to inflamed LN via CXCL9 and E-selectin [16, 118], but the pDC loss could also be due to direct infection, enhanced apoptosis or CD95 up-regulation [119-123].

Not only pDC numbers are decreased during on-going HIV-1 infection, but also the quality of the cells is suffering. They exert a reduced ability to migrate towards the CXCR4 ligand CXCL12 [124], they stimulate Treg cells to dampen HIV-1 immunity and they furthermore shift the Treg-Th17 balance [125, 126]. So far, interactions of differentially opsonized HIV-1

**3. Outlook: Impact of the HIV-1 opsonization pattern on DC function**

As follows of investigations on HIV-1 in the last 30 years, antibody responses against the vi‐ rus are not effective and cellular immune responses not powerful enough to suppress or even control HIV-1. DC, the prime inducers and regulators of immunity and tolerance, are crucial in designing modern vaccines [127-130]. Therefore, nowadays vaccine science shall combine established classical vaccine approaches with new attempts based on the expanded

Innate and adaptive immune responses are needed to generate efficient, long-lasting protec‐ tion. Immediate innate responses involve activation of the complement system, ligation of pattern recognition receptors e.g. TLRs, C-type lectins, activation of NK cells, cDC and pDC, and type I, II, as well as III interferons. For viral clearance, the optimal balance between

vaccination strategies include the use of peptides or monocyte-derived DC exposed to chemically inactivated HIV-1 and aim in designing a vaccine efficiently inducing both, cellu‐ lar and humoral immune responses [131-133]. So far, disappointing results have been ach‐ ieved in clinical trials targeting either cellular [134, 135] or humoral immunity [136, 137]. The most prominent AIDS vaccine trial so far was the RV144 in Thailand [138], which evoked

HIV-1 induces immediate responses of the immune system upon entering mucosal surfaces. There, the complement system constitutes a first line of defense against the virus. Recently, we illustrated an important role for complement opsonization of retroviruses as an endoge‐

key role in HIV-1 control is additionally substantiated by association of certain HLA class I alleles and an improved disease progression [139-141]. In view of our very recent observa‐

ral infection, particularly by enhanced infection of DC with HIV-C [41]. Thus, more efficient presentation of endogenously synthesized viral Ags via HLA-ABC [41], and ore efficient

T cells is required during the adaptive immune responses. Current HIV-1

T cell responses are crucial in controlling HIV-1 replication and their

T cell and Ab responses, but only weak HIV-specific

Role of Dendritic Cell Subsets on HIV-Specific Immunity

http://dx.doi.org/10.5772/52744

43

T cells are efficiently primed by DC during acute vi‐

preparations with pDC has not been investigated.

immunological knowledge.

and CD8+

Efficient early CD8+

strong, but transient Env-specific CD4+

tions ([58], [69]), we propose that CD8+

nous adjuvant for DC-mediated CTL-induction [58].

T cell responses [131, 138].

CD4+

CD8+

Data by Zhou et al. [99] indicate that subsequent to HIV-1 challenge, signaling via TLR7 trig‐ gers autophagy and increased IFNα production from human pDC. The IFNα secretion mediated by an autophagy-dependent pathway may play an important role for T cell trig‐ gering during HIV-1 pathogenesis.

Beside acting as pro-inflammatory cells, pDC also provide negative regulatory signals and thus induce tolerance. pDC express IDO (indoleamine 2,3-dioxygenase) and PDL-1 (pro‐ grammed death ligand; 1) which are associated with the negative modulation of T cell re‐ sponses and regulatory T cell induction [100-102].

During acute HIV-1 infection, NK cells are recruited and activated by pDC to the sites of in‐ fection and to LN due to IFNα secretion [103, 104]. IFNα was demonstrated to increase the perforin levels in NK and CD8<sup>+</sup> T cells. At the sites of infection ´DC-editing´ occurs by NK cells, since activated NK cells delete immature pDC to select for the more immunogenic ma‐ ture pDC [105-108].Beside NK cell recruitment and activation, pDC-secreted IFNα promotes maturation and migration of other DC subsets. Due to their localization, it is unlikely that pDC are involved in HIV-1 capture, transport and transmission, but they are supposed to control HIV-1 in the acute phase of infection due to their immediate antiviral and NK pri‐ ming activity.

Chronic exposure to HIV-1 leads to hyperactivation of pDC resulting in simultaneous type I IFN secretion and IDO expression. Thus, pDC concurrently exert cytotoxic and suppressive effects on T cells during chronic HIV-1 infection [109].

HIV-1 infection not only disrupts DC homeostasis within myeloid DC subsets, but also pDC homeostasis is defective during chronic HIV-1 infection. cDC and pDC are lost from blood, which correlates with high viral loads and low CD4<sup>+</sup> T cell counts [76, 110-113]. Deficiencies in pDC function were among the earliest observations of immune dysfunction in HIV-1 in‐ fection and some of the earliest studies of the ´natural IFN-α-producing cells´ (i.e. pDC) il‐ lustrated that PBMC from AIDS patients were severely compromised in their ability to produce IFN-α *in vitro* after stimulation with the virus.

Cell death and/or a failure of bone marrow progenitors to differentiate into pDC might con‐ tribute to the loss of pDC from blood of chronically infected individuals. In non-pathogenic models of SIV infection, no depletion of blood pDC was observed [114, 115] and HIV-1-posi‐ tive individuals, who are able to control infection (= long-term non-progressors) were also shown to have increased numbers of blood pDC [111].In contrast, it was described that dur‐ ing HIV-2 infection, which is highly attenuated compared to HIV-1 infection in humans, al‐ so the numbers of blood pDC is found reduced [116]. Thereby, the exact role of pDC depletion during HIV infection is not clear yet.

The depletion of cDC from the sites of infection was ascribed to a higher expression of CCR7 on the surface of cDC and a signficantly increased CCL19 expression in LN of SIV-infected animals, thus suggesting that inflamed LN lure cDC away from the sites of infection early during progressive SIV infection [117]. A similar mechanism can be imagined for pDC, which are recruited to inflamed LN via CXCL9 and E-selectin [16, 118], but the pDC loss could also be due to direct infection, enhanced apoptosis or CD95 up-regulation [119-123].

ent IFNα subsets, IFNβ, IFNκ, IFNλ and IFNω on a wide range of enveloped viruses includ‐ ing HIV-1. They additionally produce pro-inflammatory cytokines TNFα, IFNγ and IL-6 as well as chemokines CXCL-10, CCL-5 and CCL-4 among others [98]. Thereby, pDC also act

Data by Zhou et al. [99] indicate that subsequent to HIV-1 challenge, signaling via TLR7 trig‐ gers autophagy and increased IFNα production from human pDC. The IFNα secretion mediated by an autophagy-dependent pathway may play an important role for T cell trig‐

Beside acting as pro-inflammatory cells, pDC also provide negative regulatory signals and thus induce tolerance. pDC express IDO (indoleamine 2,3-dioxygenase) and PDL-1 (pro‐ grammed death ligand; 1) which are associated with the negative modulation of T cell re‐

During acute HIV-1 infection, NK cells are recruited and activated by pDC to the sites of in‐ fection and to LN due to IFNα secretion [103, 104]. IFNα was demonstrated to increase the

cells, since activated NK cells delete immature pDC to select for the more immunogenic ma‐ ture pDC [105-108].Beside NK cell recruitment and activation, pDC-secreted IFNα promotes maturation and migration of other DC subsets. Due to their localization, it is unlikely that pDC are involved in HIV-1 capture, transport and transmission, but they are supposed to control HIV-1 in the acute phase of infection due to their immediate antiviral and NK pri‐

Chronic exposure to HIV-1 leads to hyperactivation of pDC resulting in simultaneous type I IFN secretion and IDO expression. Thus, pDC concurrently exert cytotoxic and suppressive

HIV-1 infection not only disrupts DC homeostasis within myeloid DC subsets, but also pDC homeostasis is defective during chronic HIV-1 infection. cDC and pDC are lost from blood,

in pDC function were among the earliest observations of immune dysfunction in HIV-1 in‐ fection and some of the earliest studies of the ´natural IFN-α-producing cells´ (i.e. pDC) il‐ lustrated that PBMC from AIDS patients were severely compromised in their ability to

Cell death and/or a failure of bone marrow progenitors to differentiate into pDC might con‐ tribute to the loss of pDC from blood of chronically infected individuals. In non-pathogenic models of SIV infection, no depletion of blood pDC was observed [114, 115] and HIV-1-posi‐ tive individuals, who are able to control infection (= long-term non-progressors) were also shown to have increased numbers of blood pDC [111].In contrast, it was described that dur‐ ing HIV-2 infection, which is highly attenuated compared to HIV-1 infection in humans, al‐ so the numbers of blood pDC is found reduced [116]. Thereby, the exact role of pDC

The depletion of cDC from the sites of infection was ascribed to a higher expression of CCR7 on the surface of cDC and a signficantly increased CCL19 expression in LN of SIV-infected

T cells. At the sites of infection ´DC-editing´ occurs by NK

T cell counts [76, 110-113]. Deficiencies

as a linker between innate and adaptive immunity.

sponses and regulatory T cell induction [100-102].

effects on T cells during chronic HIV-1 infection [109].

which correlates with high viral loads and low CD4<sup>+</sup>

produce IFN-α *in vitro* after stimulation with the virus.

depletion during HIV infection is not clear yet.

gering during HIV-1 pathogenesis.

42 Current Perspectives in HIV Infection

perforin levels in NK and CD8<sup>+</sup>

ming activity.

Not only pDC numbers are decreased during on-going HIV-1 infection, but also the quality of the cells is suffering. They exert a reduced ability to migrate towards the CXCR4 ligand CXCL12 [124], they stimulate Treg cells to dampen HIV-1 immunity and they furthermore shift the Treg-Th17 balance [125, 126]. So far, interactions of differentially opsonized HIV-1 preparations with pDC has not been investigated.

### **3. Outlook: Impact of the HIV-1 opsonization pattern on DC function**

As follows of investigations on HIV-1 in the last 30 years, antibody responses against the vi‐ rus are not effective and cellular immune responses not powerful enough to suppress or even control HIV-1. DC, the prime inducers and regulators of immunity and tolerance, are crucial in designing modern vaccines [127-130]. Therefore, nowadays vaccine science shall combine established classical vaccine approaches with new attempts based on the expanded immunological knowledge.

Innate and adaptive immune responses are needed to generate efficient, long-lasting protec‐ tion. Immediate innate responses involve activation of the complement system, ligation of pattern recognition receptors e.g. TLRs, C-type lectins, activation of NK cells, cDC and pDC, and type I, II, as well as III interferons. For viral clearance, the optimal balance between CD4+ and CD8+ T cells is required during the adaptive immune responses. Current HIV-1 vaccination strategies include the use of peptides or monocyte-derived DC exposed to chemically inactivated HIV-1 and aim in designing a vaccine efficiently inducing both, cellu‐ lar and humoral immune responses [131-133]. So far, disappointing results have been ach‐ ieved in clinical trials targeting either cellular [134, 135] or humoral immunity [136, 137]. The most prominent AIDS vaccine trial so far was the RV144 in Thailand [138], which evoked strong, but transient Env-specific CD4+ T cell and Ab responses, but only weak HIV-specific CD8+ T cell responses [131, 138].

HIV-1 induces immediate responses of the immune system upon entering mucosal surfaces. There, the complement system constitutes a first line of defense against the virus. Recently, we illustrated an important role for complement opsonization of retroviruses as an endoge‐ nous adjuvant for DC-mediated CTL-induction [58].

Efficient early CD8+ T cell responses are crucial in controlling HIV-1 replication and their key role in HIV-1 control is additionally substantiated by association of certain HLA class I alleles and an improved disease progression [139-141]. In view of our very recent observa‐ tions ([58], [69]), we propose that CD8+ T cells are efficiently primed by DC during acute vi‐ ral infection, particularly by enhanced infection of DC with HIV-C [41]. Thus, more efficient presentation of endogenously synthesized viral Ags via HLA-ABC [41], and ore efficient cross-presentation from incoming complement-opsonized HIV-1 are mediated. In contrast, Ab-opsonization of HIV-1 weakens the CTL-induction by modulation of DC function and might influence future vaccination strategies [69].

[2] Steinman RM, Idoyaga J. Features of the dendritic cell lineage. Immunol Rev 2010;

Role of Dendritic Cell Subsets on HIV-Specific Immunity

http://dx.doi.org/10.5772/52744

45

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As shown by Lu et al. [142-144] *in vitro* and *in vivo*, DC exposed to chemically (aldrithiol-2, AT-2)-inactivated HIV or SIV induced a virus-specific CTL response. This response was strong enough to kill HIV-1-infected CD4+ T cells [142], to control the viral load in SIV-in‐ fected monkeys [143] and HIV-infected individuals [144].. The decrease of the viral load in the HIV-1-infected patients was associated with a higher amount of HIV-1-gag-specific CD8+ T cells and HIV-1-specific CD4+ T cells.

LC were described to allow more cross-priming of CD8+ T cells, while dermal DC are more specialized in primingnaive CD4+ T cells [145]. The finding that complement-opsonization of HIV prior loading of DC significantly enhanced the CD8+ T cell-stimulatory capacity of the cells in combination with using specific DC subtypes might efficiently improve future vacci‐ nation strategies and there is good reason to address DC of the skin, especially Langerhans cells, for purposes of vaccination.

A greater understanding of the innate and adaptive processes and the different functions of DC subsets to HIV-1 infection will lead to development of an effective vaccine.

### **Acknowledgements**

The authors would like to thank Nikolaus Romani and Hella Stössl for providing the trans‐ mission electron microscopic picture.

The work of the authors is supported by the Austrian Science Fund [FWF, P22165 and P24598 to DW], the Tyrolean Science Fund [TWF, project: D-155140-016-011 to WP] and the OeNB [project: 14875 to WP].

### **Author details**

Wilfried Posch, Cornelia Lass-Flörl and Doris Wilflingseder

Innsbruck Medical University, Division of Hygiene and Medical Microbiology, Innsbruck, Austria

### **References**

[1] Steinman RM, Hemmi H. Dendritic cells: translating innate to adaptive immunity. Curr Top Microbiol Immunol 2006; 311:17-58.

[2] Steinman RM, Idoyaga J. Features of the dendritic cell lineage. Immunol Rev 2010; 234:5-17.

cross-presentation from incoming complement-opsonized HIV-1 are mediated. In contrast, Ab-opsonization of HIV-1 weakens the CTL-induction by modulation of DC function and

As shown by Lu et al. [142-144] *in vitro* and *in vivo*, DC exposed to chemically (aldrithiol-2, AT-2)-inactivated HIV or SIV induced a virus-specific CTL response. This response was

fected monkeys [143] and HIV-infected individuals [144].. The decrease of the viral load in the HIV-1-infected patients was associated with a higher amount of HIV-1-gag-specific CD8+

cells in combination with using specific DC subtypes might efficiently improve future vacci‐ nation strategies and there is good reason to address DC of the skin, especially Langerhans

A greater understanding of the innate and adaptive processes and the different functions of

The authors would like to thank Nikolaus Romani and Hella Stössl for providing the trans‐

The work of the authors is supported by the Austrian Science Fund [FWF, P22165 and P24598 to DW], the Tyrolean Science Fund [TWF, project: D-155140-016-011 to WP] and the

Innsbruck Medical University, Division of Hygiene and Medical Microbiology, Innsbruck,

[1] Steinman RM, Hemmi H. Dendritic cells: translating innate to adaptive immunity.

DC subsets to HIV-1 infection will lead to development of an effective vaccine.

T cells.

LC were described to allow more cross-priming of CD8+

HIV prior loading of DC significantly enhanced the CD8+

Wilfried Posch, Cornelia Lass-Flörl and Doris Wilflingseder

Curr Top Microbiol Immunol 2006; 311:17-58.

T cells [142], to control the viral load in SIV-in‐

T cells [145]. The finding that complement-opsonization of

T cells, while dermal DC are more

T cell-stimulatory capacity of the

might influence future vaccination strategies [69].

strong enough to kill HIV-1-infected CD4+

T cells and HIV-1-specific CD4+

44 Current Perspectives in HIV Infection

specialized in primingnaive CD4+

cells, for purposes of vaccination.

mission electron microscopic picture.

**Acknowledgements**

OeNB [project: 14875 to WP].

**Author details**

Austria

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**Chapter 3**

**Hematopoietic Stem Cell Transplantation in HIV**

In the highly active antiretroviral therapy (HAART) era, the survival of HIV infected pa‐ tients has improved. Opportunistic infections and AIDS related syndromes in these individ‐ uals have declined (Palella et al, 1998). HIV infected individuals have an increased tendency to develop malignancy. These include a number of non-AIDS defining malignancies, as well as the AIDS defining malignancies which are Kaposi sarcoma, invasive cervical cancer and non-Hodgkin Lymphoma (NHL). Among the NHL group, the incidence of systemic NHL, CNS Lymphoma and primary effusion lymphoma are increased in this population. Malig‐

The incidence of NHL increases with progressive immunosuppression in HIV-infected pa‐ tients. The majority of these cases are intermediate or high-grade and almost all are diffuse large B cell (immunoblastic variant) or Burkitt-like lymphomas. The incidence of Hodgkin lymphoma (HL) is also increased in the HIV positive population (Bigar R et al, 2006) though it is not an AIDS defining illness. Acute myeloid leukemia may also occur with higher fre‐ quency in the setting of HIV infection (Grulich A et al, 2007). NHL and HL occurring in HIV infected individuals are characterized by an aggressive clinical course with an advanced

In the pre-HAART era, the standard treatment for AIDS associated NHL was low dose che‐ motherapy. It was thought that they would be unable to tolerate intensive chemotherapy be‐ cause of the underlying immunodeficiency. Randomized trials of standard doses of combination chemotherapy versus reduced doses revealed inferior results in the standard dose arm due to increased hematologic toxicity and infections (Kaplan LD et al, 1997). In the post-HAART era, patients were treated more aggressively due to improved hematologic re‐ serve in patients on HAART. Patients are now treated similar to non HIV NHL patients.

> © 2013 Nathwani; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

nancies continue to be an important cause of mortality in these individuals.

**Infected Patients**

http://dx.doi.org/10.5772/52686

stage at presentation (Levine AM, 2000).

Additional information is available at the end of the chapter

Nitya Nathwani

**1. Introduction**
