**Immunology**

**Chapter 3**

**Provisional chapter**

**Immune Disorders in HIV-Infected Patients Coinfected**

**Immune Disorders in HIV-Infected Patients Coinfected** 

In Russia, more than half of HIV-infected people are coinfected with hepatitis C. Both viruses interact with the immune system compounding the disease course. HIV infection accelerates the onset of hepatitis-mediated liver fibrosis and cirrhosis. Hepatitis C slows down the recovery of CD4+ T-lymphocytes during antiretroviral treatment and fuels the already intense chronic inflammation. In the present review, we discuss coinfection prevalence and reasons for its abundance, provide extensive coverage of the known mechanisms that give rise to the detrimental health effects in HIV/hepatitis C-coinfected patients, and report our own data on the double infection consequences in people with

**Keywords:** HIV infection, hepatitis C, HIV/HCV coinfection, innate immunity, adaptive immunity, discordant immunologic response, highly active antiretroviral therapy

More than any other infectious disease, HIV infection claims to be called "the coinfection illness" [1]. Coinfections can significantly change the illness pattern and the immune activation profile [2–4] and typically lead to the rise in morbidity and mortality [5–7]. The coinfection most often associated with HIV is hepatitis C virus (HCV) infection. This is due to the worldwide prevalence of both illnesses (there are approximately 40 million HIV-infected and about 120 million HCV-infected subjects worldwide) and the overlap in infection transmission routes [8, 9]. In Western Europe and the United States, the proportion of hepatitis C chronically infected patients among HIV-positive people is 25–30% [10], and in Eastern Europe, it is more than 50% [11]. In Russia, the increase in injection drug use has led to a significant rise

> © 2016 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.

© 2018 The Author(s). Licensee IntechOpen. 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.

DOI: 10.5772/intechopen.76810

**with Hepatitis C Virus**

**with Hepatitis C Virus**

http://dx.doi.org/10.5772/intechopen.76810

**Abstract**

**1. Introduction**

Konstantin Shmagel and Evgeniya Saidakova

Konstantin Shmagel and Evgeniya Saidakova

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

discordant immunologic response to treatment.

#### **Immune Disorders in HIV-Infected Patients Coinfected with Hepatitis C Virus Immune Disorders in HIV-Infected Patients Coinfected with Hepatitis C Virus**

DOI: 10.5772/intechopen.76810

Konstantin Shmagel and Evgeniya Saidakova Konstantin Shmagel and Evgeniya Saidakova

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.76810

#### **Abstract**

In Russia, more than half of HIV-infected people are coinfected with hepatitis C. Both viruses interact with the immune system compounding the disease course. HIV infection accelerates the onset of hepatitis-mediated liver fibrosis and cirrhosis. Hepatitis C slows down the recovery of CD4+ T-lymphocytes during antiretroviral treatment and fuels the already intense chronic inflammation. In the present review, we discuss coinfection prevalence and reasons for its abundance, provide extensive coverage of the known mechanisms that give rise to the detrimental health effects in HIV/hepatitis C-coinfected patients, and report our own data on the double infection consequences in people with discordant immunologic response to treatment.

**Keywords:** HIV infection, hepatitis C, HIV/HCV coinfection, innate immunity, adaptive immunity, discordant immunologic response, highly active antiretroviral therapy

#### **1. Introduction**

More than any other infectious disease, HIV infection claims to be called "the coinfection illness" [1]. Coinfections can significantly change the illness pattern and the immune activation profile [2–4] and typically lead to the rise in morbidity and mortality [5–7]. The coinfection most often associated with HIV is hepatitis C virus (HCV) infection. This is due to the worldwide prevalence of both illnesses (there are approximately 40 million HIV-infected and about 120 million HCV-infected subjects worldwide) and the overlap in infection transmission routes [8, 9]. In Western Europe and the United States, the proportion of hepatitis C chronically infected patients among HIV-positive people is 25–30% [10], and in Eastern Europe, it is more than 50% [11]. In Russia, the increase in injection drug use has led to a significant rise

© 2016 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. © 2018 The Author(s). Licensee IntechOpen. 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.

in the prevalence of HIV/HCV coinfection. Its level among drug users reaches 93% [12]. The problem is complicated by the rise in non-AIDS-defining morbidity and mortality in HIV/ HCV-coinfected subjects [13, 14].

with liver cirrhosis have a reduced CD4+ T-cell count [40, 41]. Most researchers state that HIV infection, accompanied by a profound depletion in the CD4+ T-lymphocyte pool, is a prominent mediator of the accelerated liver fibrosis development in HIV-/HCV-coinfected people [42–44]. Based on those results and the opinions of leading specialists, the European AIDS Clinical Society recommends the early administration of highly active antiretroviral therapy (ART) to HCV-coinfected patients not only to optimize their hepatitis C management but also

Immune Disorders in HIV-Infected Patients Coinfected with Hepatitis C Virus

http://dx.doi.org/10.5772/intechopen.76810

47

The main cellular element involved in the process of hepatic tissue fibrosis is the liver stellate cell (LSC) [46–49] located around the sinuses and usually not showing high activity until the organ is damaged [50, 51]. However, various destructive processes in the liver are accompanied by the reaction of hepatocytes, endotheliocytes, and Kupffer cells to produce various humoral factors [52]. Of those, TGF-β1 [53, 54] and PDGF (platelet-derived growth factor) have the most pronounced effect on LSC [52, 55]. Both cytokines induce LSC activation and differentiation into myofibroblast-like cells, which actively synthesize extracellular matrix proteins [56]. However, it should be noted that TGF-β1 and PDGF blood concentrations (as opposed to analyzing the hyaluronic acid or hepatocytes' growth factor content) have no high diagnostic value for the detection of fibrosis [57–60]. Moreover, it has recently been established that HIV influences the liver by infecting hepatocytes and liver stellate cells [61].

Protection against HCV is implemented by various factors with an important role for interferons, natural killer (NK) cells, neutralizing antibodies, and T-lymphocytes. Type I interferons (IFN-α and IFN-β) and type III interferon (IFN-λ) are synthesized in response to the virus and induce interferon-stimulated gene (ISG) expression [62, 63]. In the cytosol, the pathogen's RNA is detected by the RIG-I (retinoic acid-inducible gene I) sensors, protein kinase R, and MDA5 (melanoma differentiation-associated protein 5). The first two mediate the interferon response at the early stages of the disease, and the third one mediates at the later infection phase [64, 65]. In endosomes, the virus is primarily detected by Toll-like receptor 3 (TLR3) that also triggers the IFN production and the ISG expression [66]. In hepatocytes of HCVinfected patients, the viral RNA and ISGs' mRNA are detected simultaneously, which confirms the connection between the cell genetic response and the presence of the pathogen [67]. The result of the activated ISG status in HCV infection leads to viral replication inhibition [68, 69]. However, prolonged ISG expression has a negative effect on the process of HCV spontaneous elimination [70, 71] and on the results of interferon and ribavirin combination

NK cells play an important role in the pathogenesis of an HCV infection. It was found that in the healthy liver they represent the majority of the innate immune cells [74]. In the acute phase of the disease, NK cells affected by the virus are activated, produce IFN-γ, and perform cytotoxic functions [75]. In the chronic infection phase, IFN-γ and tumor necrosis factor (TNF)-α synthesis are reduced [76–78] even though the NK cell cytotoxic potential remains high [79, 80]. Since the protective effect of IFN-γ was demonstrated in HCV-infected hepatoma cells [81] and in experiments with chimpanzees given primary and repeated infections [82], it is

to slow down the development of fibrosis [45].

**3. Anti-HCV immunity in HIV/HCV coinfection**

therapy [72, 73].

There is considerable evidence that HIV infection adversely affects the course of a hepatitis C infection. When HIV/HCV coinfection is compared with HCV monoinfection, a more rapid fibrosis [15, 16] and liver cirrhosis [16, 17] are observed. Coinfected subjects also have an increased risk of hepatocellular carcinoma, which occurs at an earlier age and in a shorter time interval after HCV infection [18–20]. It was found that HIV/HCV-coinfected patients compared to HCV-monoinfected patients were more resistant to interferon therapy. In HIV-seronegative subjects infected with HCV genotype 1, 50–80% can achieve a complete recovery. However, in HIV-seropositive individuals coinfected with the same HCV type, interferon therapy is successful only in 20–35% of patients [21]. This accounts for the increased mortality rate among HIV-/HCV-coinfected patients when compared with HIV-monoinfected patients [22, 23].

Less is known about the effect of hepatitis C on the natural course of HIV infection. Among the negative influences, one can point to direct viral effects, hepatocyte destruction by immunocompetent cells, hepatic cell apoptosis, immune activation, and specific antiviral immune response alterations [24–26]. The complexity of the problem is largely due to the lack of knowledge about the biology of both HIV and HCV. It remains unknown whether the viruses interact with each other and in what ways that interaction might be expressed.
