**1. Introduction**

Acquired immunodeficiency syndrome (AIDS) evolved into a pandemic in less than a decade since the first reports of a new set of symptoms that included severe opportunistic infections and unusual neoplasms, particularly Kaposi's sarcoma, in homosexual men [1]. Nearly 30 years since the discovery of the causative agent [2, 3], human immunodeficiency virus (HIV) cannot still be eradicated, nor is there sight of a safe and effective prophylactic vaccine in the horizon. Infection with either virus type invariably leads to AIDS; however, the less pathogenic HIV-2 stains have been geographically restricted mainly to West Africa, whilst the more virulent HIV-1 strains have spread around the globe causing the AIDS pandemic [4]. The worst afflicted region is sub-Saharan Africa, where in a few countries more than one in five adults is infected with the virus; at the same time, the epidemic is spreading most rapidly in Eastern Europe and Central Asia, where the number of people living with HIV increased by 250% between 2001 and 2010 [5]. Worldwide, an estimated 34 million people, including 3.4 million children, were living with HIV at the end of 2010, while the related deaths and new infections were 1.8 and 2.7 million, respectively [5].

Despite these frightening numbers, which are indicative of a growing epidemic far from the UNAIDS vision of zero AIDS-related deaths and zero new infections, considerable progress has undoubtedly been noted in basic and clinical research in the field of HIV/AIDS [6]; we now understand most aspects of HIV pathogenesis and have identified targets suitable for therapeutic intervention. The introduction of combination antiretroviral therapy (ART) in 1996 revolutionized patient care and brought about a significant reduction in AIDS-related morbidity and mortality; HIV infection has been transformed into a chronic condition that is generally controllable with lifelong treatment, at least in the developed world where treatment is available. At the forefront of current anti-HIV research, CCR5 inhibitors represent a novel drug class that broadens the therapeutic options of patients, which are

© 2012 Anastassopoulou, licensee InTech. This is an open access chapter 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. © 2012 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.

currently limited by chronic toxicities or by the presence of resistance to conventional antiretrovirals targeting ever mutating virus-encoded structures.

Chemokine Receptors as Therapeutic Targets in HIV Infection 117

**2.2. Physiological roles of the main coreceptors** 

inflammation and development [28].

valid target for pharmacological blockade.

*CCR5*Δ

CCR5 and CXCR4 are two structurally related, heptahelical chemokine receptors that belong to different classes [C-C and CXC, respectively, based on the position of the two conserved cysteine (Cys) residues in their N-termini (Nt)] of the superfamily of G protein-coupled receptors (GPCRs) (reviewed in [13, 23-25]). About half of the drug targets in the pharmaceutical industry are GPCRs, which also, not coincidentally, comprise the largest family of cell-surface receptors [26]. GPCRs become activated by chemokines, small (8-10 kDa) soluble protein ligands that are either promiscuous or specific for a given receptor. Once activated by such extracellular signals, GPCRs undergo conformational changes that trigger the intracellular signal transduction cascade; these series of events begin with the rapid phosphorylation by G protein-coupled receptor kinases (GRKs) predominantly on serine (Ser) and threonine (Thr) residues within the C-tail and third intracellular loop and continue with the activation of heterotrimeric G proteins [27]. In this mode, chemokines and their receptors control cell migration associated with routine immune surveillance,

CCR5, in particular, appears to play a role in the initiation of adaptive immune responses and the trafficking of effector cells to sites of infection and inflammation as indicated by its expression profile on several effector T cell subsets and antigen-presenting cells, including macrophages, immature dendritic cells and Langerhans cells (reviewed in [22, 29, 30]). Nonetheless, the lack of expression of this gene due to a deletion polymorphism known as "delta32" does not appear to have any deleterious effects; in fact, heterozygosity for the

*32* allele is generally associated with delayed disease progression, and homozygosity

with incomplete protection from HIV transmission (reviewed in [31]). The observation that its congenital absence does not lead to any overt pathology suggested that CCR5 might be a

CXCR4, on the other hand, and its single known ligand SDF-1/CXCL12 are both highly conserved [13]; they play an essential role during embryonic development and in several major processes in the adult, including hematopoiesis, leukocyte trafficking in the adaptive immune system, and vascularization [22]. CXCR4 knockout mice show hematopoietic and cardiovascular defects during embryogenesis and die *in utero*; mice lacking SDF-1/CXCL12 are characterized by deficient B-lymphopoiesis and myelopoiesis and abnormal neuronal and cardiovascular development [13]. Clinically tested CXCR4 inhibitors AMD3100, which lacked oral bioavailability, and AMD070 caused significant leukocytosis (reviewed in [22]). The non-cyclam antagonist AMD070 (or AMD11070) is currently in Phase II clinical trials as an HIV cell-entry inhibitor [32]. The development of AMD3100 (by AnorMED) for use in the treatment of HIV infection was terminated, but further studies led to a new indication for this drug; AMD3100 (now Plerixafor, Genzyme) has been approved by the US Food and Drug Administration (FDA) for autologous transplantation in patients with non-Hodgkin's lymphoma and multiple myeloma [32]. The fact that Plerixafor is well tolerated in the developed organism minimizes the concerns of antagonizing such a crucial receptor/ligand axis in mature individuals. CXCR4 antagonists could be used in combination with

This chapter focuses on describing the scientific rationale that led to the development of coreceptor inhibitors as a new class of host-targeted antiretroviral agents. This description entails a revision of the biology of coreceptor usage during HIV entry into target cells and viral tropism during the course of infection. The various approaches undertaken to pharmaceutically target the most commonly used coreceptor, CCR5, will then be described, with a special focus on small molecule CCR5 inhibitors (also termed "CCR5 antagonists") and their mechanism of action. The current status of the small molecule CCR5 inhibitor pipeline, with emphasis on the generation of resistance, including *in vitro* and *in vivo* HIV escape pathways and mechanisms, will be presented, while implications as well as future perspectives for the clinical use of CCR5 inhibitors will be discussed.
