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CCR5 antagonism in HIV infection: ways, effects, and side effects

Corbeau, Pierrea,b,c; Reynes, Jacquesc,d,e

doi: 10.1097/QAD.0b013e32832e71cd
Editorial Review

aUnité Fonctionnelle d'Immunologie, CHU de Nîmes, Nîmes, France

bInstitut de Génétique Humaine, CNRS UPR1142, France

cFaculté de Médecine, Université Montpellier 1, France

dService des Maladies Infectieuses et Tropicales, CHU de Montpellier, France

eUMR145, Montpellier, France.

Received 5 December, 2008

Revised 6 April, 2009

Accepted 21 May, 2009

Correspondence to Prof Jacques Reynes, Service des Maladies Infectieuses et Tropicales, Hôpital Gui de Chauliac, 80 avenue Augustin Fliche, 34295 Montpellier cedex 5, France. Tel: +33 4 67 33 72 20; fax: +33 4 67 33 75 51; e-mail:

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New drugs are needed to improve the convenience of anti-HIV therapy, to reduce its toxicity, and to enhance its activity against both wild-type and resistant viral strains. A number of promising compounds are in development both in already existing classes (reverse transcriptase, protease, and fusion inhibitors) and in new classes (integrase inhibitors). Yet, the identification of drugs that exploit new targets in HIV life cycle remains an important therapeutic objective. The discovery that the C-C chemokine receptor CCR5 is the main coreceptor for HIV-1 [1–5], in addition to the CD4 receptor, has opened new therapeutic possibilities. Thus, the first CCR5 inhibitor, maraviroc, has been approved for use in HIV-infected individuals in 2007. In this article, we will briefly review the biology of CCR5, discuss the virological and immunological consequences of blocking CCR5, and present alternative strategies to neutralize this coreceptor.

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CCR5, chemokine receptor and HIV coreceptor

CCR5 is a G-protein-coupled receptor (GPCR) able to bind C-C chemokines, mainly CCL3 (MIP-1α), CCL4 (MIP-1β), CCL5 (RANTES) [6], but also CCL2 (MCP-1), CCL7 (MCP-3), CCL8 (MCP-2), CCL11 (eotaxin-1), and CCL13 (MCP-4) [7,8]. CCL7 and CXCL11 (I-TAC) have been reported to be natural antagonists for CCR5 [7,9]. CCL3, CCL4, and CCL5 have been identified in 1995 as major macrophage-tropic HIV-1 suppressive factors released by CD8+ T cells [10]. In 1996, CXCR4, a chemokine receptor which only known ligand is the CXC-chemokine CXCL12 (SDF-1), was identified as the coreceptor for T-cell line-tropic HIV-1 strains [11], in addition to the CD4 receptor. Soon after, CCR5 was identified as the coreceptor for macrophage-tropic HIV-1 strains [1–5]. In addition to CCR5 and CXCR4, other chemokine receptors and even orphan GPCR, including CCR2b, CCR3, CCR8, CCR9, CX3CR1, CXCR6, and APJ, can be used as coreceptors by HIV in vitro, but their role remains uncertain in vivo. As all GPCR, CCR5, and CXCR4 comprise an extracellular N-terminus, seven membrane-spanning domains linked by three extracellular and three intracellular loops, and a cytoplasmic C-terminal tail (Fig. 1). CD4 and CCR5 are coexpressed on CD4+ T cells, particularly on Th1 cells, on dendritic cells, and on monocytes and macrophages. The importance of CCR5 in in-vivo HIV-1 infection is underlined by the fact that individuals homozygous for the CCR5-Δ32 allele, defined by a 32 base pair deletion causing a frame shift and premature stop codon, which encodes a truncated protein product that is not expressed at the cell surface, are usually resistant to the infection [12,13]. CCR5-using (R5) HIV-1 strains can be detected at all stages of infection, whereas CXCR4-using (X4) and CCR5 and CXCR4-using (R5X4) strains are only isolated from half to one-third of the patients, mostly at late stages of the disease [14]. A study reported in treatment-naive individuals the exclusive presence of R5 strains in about 90% of individuals with CD4 cell counts over 200/μl, in about 70% of individuals with CD4 cell counts between 25 and 200/μl, and in about 50% of individuals with CD4 cell counts below 25/μl [15]. The predominance of R5 strains early in the disease and the emergence of X4 strains in some patients but not in others later in the disease, which has been correlated with rapid disease progression [16], are poorly understood phenomena. Various factors might account for the predominance of R5 strains over X4 strains. Some authors argued that the humoral [17] or the cytotoxic T-cell [18] response being more efficient against X4 strain than against R5 strains, the immune system must be weakened by R5 strains for the X4 strains to be able to expand. Other authors proposed that the cause is a higher replicative capacity of R5 strains. The reason for that might be a higher CD4+ T-cell surface density for CCR5 than for CXCR4, a closer association of CCR5 with CD4 [19] eventually within membrane raft [20], a stronger gp120-coreceptor affinity in R5 strains [21], or a higher cytopathogenicity of X4 strains [22].

Fig. 1

Fig. 1

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gp120 binding to CCR5

Mutagenesis, inhibition with peptides and monoclonal antibodies, and receptor hybrids between CCR5 and other C-C chemokine receptors have shown that the NH2-terminal domain, particularly the 20 first amino acids by interacting with gp120 ‘bridging sheet’ and V3 stem, and the extracellular loops of CCR5, particularly the second one by interacting with V3 crown, contribute to HIV binding, fusion, and entry. Interestingly, antibodies specific for the NH2-terminal domain were more efficient in blocking gp120–CCR5 binding, whereas antibodies specific for the second extracellular loop were more efficient in blocking HIV infection. Of note, there is some variability among HIV-1 strains in the way they interact with CCR5. Thus, differences in gp120 binding to CCR5 between R5 and R5X4 strains [23], and between clade B and nonclade B strains [24] have been reported. Even among clade B isolates, variations exist that may have consequences on CCR5 inhibitor efficiency, as discussed below. The overlap between the gp120 binding site and the C-C chemokines binding site is only partial, so that some CCR5 inhibitors block C-C chemokine binding, but others do not. It is believed that there are multiple conformational states of CCR5, and that the association with another GPCR, as discussed below, or with a ligand could induce a conformational change. From a quantitative point of view, Kuhmann et al. [25] have estimated that four to six CCR5 molecules must assemble around a virion to form a complex required for infection.

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Cell surface CCR5 expression

CCR5 is expressed on some hematopoietic cells, in the central nervous system on neurons, astrocytes, and microglia, on epithelium, endothelium, vascular smooth muscle, and fibroblasts [26]. Among hematopoietic cells, CCR5 can be evidenced on immature dendritic cells, on monocytes/macrophages, on CD8+ T cells, and on CD4+ T cells, particularly on memory T cells and on Th1 cells [27–29]. On CD4+ T cells 4000 to 24 000 CCR5 molecules may be numerated per cell. This CD4+ T-cell surface CCR5 density is constant over time for a given individual. That is to say that one can discriminate between low and high CCR5 expressors [30]. Nucleotide polymorphisms in the CCR5 promoter, associated or not with differences in CCR5 cell surface expression, have been linked to disease progression [31–33]. CCR5-binding chemokines induce endocytosis of the chemokine receptor into early endosomes through clathrin-coated pits and through caveolae [34,35]. Afterwards, CCR5 is recycled to the cell surface (Fig. 1). In the absence of ligand, the chemokine receptor has a constitutive turnover with a half-life of a few hours [35]. The fact that CD4+ T-cell surface CCR5 density is inversely correlated with the amount of CCL5 mRNA present in peripheral blood mononuclear cells [36], argues for a model in which the blood concentration of circulating CCR5-binding chemokines regulates the level of cell surface CCR5. In support of this notion, the administration to healthy volunteers of a CCR5 antagonist which disrupts CCR5–chemokines interaction resulted in an increase in CD4+ T-cell surface CCR5 density [36].

CCR5 could be anchored to plasma membrane lipid rafts through the palmitoylated cysteine residues located in its C-terminal domain [37]. CCR5 molecules form clusters in microvilli associated with CD4 molecules [38,39]. An additional element of complexity has been added with the report that wild-type CCR5 could polymerize, not only with itself [40], but also with its truncated Δ32 form [41], with other chemokine receptors, as for instance with CCR2 [42], and even with other GPCR that are not chemokine receptors, such as opioid receptors [43]. The consequences of such potential dimerizations on CCR5 conformation, on CCR5–gp120 binding, and on CCR5 signaling remain to be unveiled.

CCR5 expression on CD4+ T cells is up-regulated under antigen activation [44], but down-regulated under CD28 stimulation [45]. Cytokine stimulation may also modify positively (IL-2, IL-15, IFNγ) or negatively (IL-4, IL-10, IL-16) CCR5 expression [46]. Finally, progesterone [47] has been reported to down-regulate CCR5. Of note, CD4+ T-cell surface CCR5 density is increased during primary HIV-1 infection, but remains thereafter stable over time in HIV-1-infected individuals, at least during the asymptomatic phase [30]. By contrast, the percentage of CD4+ T cells expressing CCR5 is not stable over time for a given individual, either infected or not.

Of note, CD4+ T-cell surface density is particularly high in gut-associated lymphoid tissue [48]. This is of particular interest since this tissue, which contains the majority of the T lymphocytes, appears to be a main target of the virus [49] and emphasizes the therapeutic interest of blocking CCR5.

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Role of the CCR5 receptor in physiology

CCR5 is not only a chemokine receptor able to drive towards CC-chemokines cells that express it at their surface. It is also a coactivation receptor.

In mice, CCL5 induces the expression of activation markers at the surface of primary murine T cells in vitro, and its in-vivo administration along with an antigen increases the proliferative response of CD4+ T cells to this antigen as well as their level of cytokine production [50]. In humans, CCL5 is also able to activate T clones, to induce CCL3 and IFNγ production, and cell division [51,52]. The three major CCR5 ligands – CCL3, CCL4, and CCL5 – increase IL-2 production and cell proliferation of antigen-stimulated human T cells [53]. Recently, Contento et al. [54] have evidenced that during the interaction between a T-cell and an antigen-presenting cell, CCR5 is recruited into the immunological synapse in which it delivers costimulatory signals. CCR5 has also been involved in the recruitment of naive CD8+ T cells to antigen-presenting dendritic cells [55,56].

More specifically, CCR5 has been linked to cellular immunity (Fig. 2). Actually, CCR5 is expressed on Th1 cells that produce IL-2 and IFNγ, and favor cellular rather than humoral immunity [29]. Moreover, IL-2 and IFNγ up-regulate CCR5 expression, whereas the type 2 cytokine IL-10 down-regulates it [57]. And finally, CCL3, CCL4, and CCL5 that are produced by Th1 cells [58] favor CD4+ T-cell differentiation into Th1 cells [59], and activate macrophages in synergy with IFNγ, acting as type 1 cytokines [60]. Accordingly, Th1-type response is depressed in CCR5-deficient mice [61].

Fig. 2

Fig. 2

Yet, CCR5 seems to be physiologically dispensable. Mice with a targeted deletion of the CCR5 gene developed normally in a pathogen-free environment, and presented with limited disturbance in macrophage and T-cell chemokine productions resulting in an enhanced delayed-type hypersensitivity and humoral response [62]. Likewise, humans homozygous for the CCR5-Δ32/Δ32 genotype, who express no cell surface CCR5 molecules, have been reported to be in healthy clinical conditions, except for a higher prevalence of hypertension [63,64]. This fact might be the consequence of the redundancy of the chemokine–chemokine receptor network [65]. Although CCR5 seems dispensable for normal health, this C-C chemokine receptor has been involved in many pathological situations.

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Role of the CCR5 receptor in diseases

Role of the CCR5 receptor in infectious diseases

HIV is not the only pathogen producing a molecule able to bind to and to signal through CCR5. Actually, mycobacterial Hsp70 [66] and cyclophilin-18 from Toxoplasma gondii [67] do the same, and like HIV, vaccinia virus could induce CCR5 signaling to support its one replication [68]. CCR5 has also been involved in the immune defense against other transmissible agents. Thus, the immune response to Listeria monocytogenes [62], Cryptococcus neoformans [69], T. gondii [70], influenza A virus [71], herpes simplex virus type 2 [72], Trypanosoma cruzi [73], Chlamydia trachomatis [74] are impaired in CCR5-deficient mice. In humans, genetic variants of the CCR5 promoter have been associated with severe bronchioloitis caused by respiratory syncytial virus [75], and CCR5 deficiency with increased risk of symptomatic infection, and disease severity, with two Flaviviridiae, West Nile virus [76], and tickborne encephalitis virus [77]. Moreover, some authors have reported that the CCR5-Δ32 phenotype was increased in hepatitis C [78] and that in case of infection, patients homozygous for CCR5-Δ32 presented with high viral loads [78], high serum alanine-aminotransferase levels [63], and impaired virological response to IFNα [79]. Yet, these observations have been contradicted by other works [80–84], and the putative role of CCR5 in HCV infection remains to be determined. Interestingly, CCR5 might play a pathogenic role in diseases mediated by the antimicrobial immune response. For instance, CCR5-/- mice have been shown to be less susceptible to the cerebral form of malaria because of a defect in leukocyte accumulation in the brain [85], to exhibit a reduced severity of demyelination under infection with a neurotropic coronavirus, which correlated with a reduced macrophage traffic into the central nervous system [86], and to be protected from lipopolysaccharide-induced endotoxemia [62]. Altogether these observations evidence that on one hand CCR5 is a part of the immune defense against some infectious agents, but that on the other hand CCR5 participates in the tissue damage caused by the immune response triggered by other infectious agents. In addition, as the recruitment to microbe induced-lesions of regulatory T cells (Treg), that down-regulate effector T-cell functions, is CCR5-dependent, the absence of CCR5 may be beneficial in infections in which Treg cells are involved [87]. Thus, the relationship between CCR5 and lymphocyte activation appears to be ambivalent. At the surface of effector T cells, CCR5 is a coactivation receptor, whereas at the surface of Treg it will promote the attraction of regulatory T cells able to inhibit effector T cells.

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Role of the CCR5 receptor in noninfectious diseases

CCR5 is suspected to mediate Th1-type immune response and infiltration of mononuclear cells in the lesions of various autoimmune diseases, particularly in multiple sclerosis, type 1 diabetes, colitis, and rheumatoid arthritis. For instance, many facts argue for a responsibility of CCR5 in the recruitment of monocytes and Th1 cells towards the inflamed joints in which CCL3, CCL4, and CCL5 are produced, in the course of rheumatoid arthritis. As a consequence, individuals heterozygous for the Δ32 deletion in the CCR5 gene could be partially protected from rheumatoid arthritis [88–90], and particularly from severe forms of rheumatoid arthritis [91].

The development of atherosclerosis seems to be facilitated by CCR5 expression. Thus, in atherosclerosis-prone mice, deficiency in CCR5 is protective [92,93], and a CCR5 antagonist has been shown to reduce plaque formation [94]. The protective effect includes the lack of recruitment of macrophages to the plaque and the presence of endothelial progenitor cells [92–94].

CCR5 has been involved in graft rejection. Thus, Fischereder et al. [95] observed an increase in renal transplant survival in homozygous CCR5-Δ32 patients, and Abdi et al. [96] a reduced risk of acute renal transplant rejection in recipients who were homozygous for the CCR5-59029-A/G mutation in the CCR5 promoter, linked to low CCR5 expression. Likewise, it has recently been shown in a primate cardiac allograft model that CCR5 blockade prolonged graft survival [97].

CCR5-Δ32 has also been associated with reduced risk of asthma by Hall et al. [98]. Yet, this observation has been contradicted by other authors [99–101].

Finally, CCR5 plays a double game in cancer. On one hand, CCR5 has protumoral effects. CCR5 at the surface of cancer cells might deliver signals of proliferation [102] motility, invasion, and metastasis [103]. On the other hand, antitumoral effects of CCR5 have been described. Thus, CCR5 may participate in the antitumoral immune response mediated by CCR5-expressing leukocytes [104]. More directly, CCR5 has been involved in cancer progression by Mañes et al. [105]. These authors have evidenced a reduction in survival in patients with breast cancer bearing the CCR5Δ32 allele. They propose that CCR5 could activate p53 transcriptional activity through p38 MAPK phosphorylation and could thereby slow tumor cell growth [105].

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CCR5 inhibitors

Three kinds of CCR5 inhibitors have been or are being developed.

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Small-molecule CCR5 antagonists

Small molecules have been identified that are able to exert a noncompetitive, allosteric, inhibition on CCR5 function as an HIV-1 coreceptor. They are thought to bind to transmembrane domains of CCR5 and thereby to impair gp120 interaction with the coreceptor [106,107]. These CCR5 antagonists also hinder the interaction between CCR5 and its natural ligands [108]. Maraviroc is the first CCR5 antagonist approved for clinical use in HIV-infected persons. The efficacy of maraviroc was established in clinical trials (MOTIVATE 1 and 2) involving HIV-1-infected, antiretroviral-experienced persons with persistent R5 viremia. In a combined analysis of the two trials, maraviroc together with optimized background therapy (OBT) resulted in an about 1 log10 decrease in HIV-1 RNA levels, compared with OBT only [109]. Other CCR5 antagonists are under study, as vicriviroc in phase III development, whereas the trials with a third antagonist, aplaviroc, have been ended because of liver toxicity [110]. Maraviroc and vicriviroc have been well tolerated [111].

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Anti-CCR5 antibodies

Humanized monoclonal antibodies specific for the amino-terminal domain and/or the second extracellular loop of CCR5 and able to compete with gp120 binding are also being developed. Two anti-CCR5 monoclonal antibodies have been tested in HIV-infected individuals, PRO140 [112] and HGS004 [113]. At low concentration, PRO140 inhibits HIV without blocking CCR5 response to chemokines, whereas HGS004 prevents viral infection and chemokine signaling. Their antiviral activity is similar to that of the CCR5 antagonists. Of note, antibodies and small-molecule antagonists do not share the same mode of inhibition and there is no cross-resistance between these two classes of CCR5 inhibitors.

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Modified chemokines

As chemokines display a short half-life in circulation (<10 min) [114], they have been N-terminally modified to be used as CCR5 blockers. Thus modified, they also cause prolonged CCR5 internalization. Yet, some of them induce CCR5 signaling. CCL5 analogs are currently tested as topical microbicide in animal models [115].

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Potential consequences of blocking CCR5

Viral consequences

Positive consequences: anti-HIV effects

CCR5 antagonists have been described as entry inhibitors. As a matter of fact, they display three additional antiviral effects (Fig. 3). First, they inhibit syncitia formation, the deadly fusion between infected and noninfected CD4+ cells that has been proposed as one of the causes of CD4+ T-cell decline in infected patients. Second, CCR5 antagonists block gp120-induced apoptosis, another proposed cause of CD4+ T-cell destruction. Of note, the intensity of gp120-induced apoptosis has been linked to cell surface CCR5 density [116]. Finally, CCR5 antagonists have been shown to be able to enter CD4+ T cells and to prevent the intracellular interaction between gp120 and CCR5 that results in single cell lysis [117].

Fig. 3

Fig. 3

Consequently, CCR5 antagonists should not only block HIV replication, but in addition lower the cytopathogenicity due to any residual viral replication.

Lastly, CCR5 antagonists act in synergy with other antiretroviral drugs to inhibit in-vitro HIV replication [118]. This is consistent with the observation that the response to classical treatment is linked to CD4+ T-cell surface CCR5 density [119,120]. CCR5 occupancy by the antagonist should result in a decrease in the functional density of cell surface CCR5, and thereby in an increase in antiretroviral therapy efficiency. This might be particularly true for the fusion inhibitors, since CCR5 antagonists might expand the time during which gp41 is accessible to these drugs [121]. Accordingly, the efficiency of the fusion inhibitor enfuvirtide has recently been inversely correlated with CD4+ T-cell surface CCR5 density [122].

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R5 to X4 switch

A major concern is the risk to provoke an R5 to X4 switch by treating patients with CCR5 antagonists. This concern is based on the idea that, in a human-infected organism, there is a competition between the various HIV strains. Between R5 and X4 strains, the competition might be for the target cells, since 34–76% of CD4+ T cells coexpress CCR5 and CXCR4 [123]. Yet, up to 60% of CXCR4+CD4+ T cells are CCR5-, so that it could be argued that X4 strains might expand without inhibition exerted by R5 production [123]. As above-mentioned, the reasons for a naturally occuring change in coreceptor usage in the course of HIV-1 disease are poorly understood. In particular, it is not clear whether a low level of CCR5 expression may favor this event. According to the competition dogma, a decrease in CCR5 expression might induce the switch by releasing the pression on X4 strains. On the contrary, one can reason that a high CCR5 expression results in a high R5 production and a high incidence of mutations, among which some responsible for R5 to X4 change. Conflicting studies exist on the link between heterozygosity for CCR5-Δ32, which is responsible for a low level of CCR5 expression, and a high incidence of coreceptor switch. On one hand, de Roda Husman [124] observed that R5 to X4 switch is delayed in CCR5-Δ32 heterozygotes as compared with CCR5wt homozygotes. But on the other hand, D'aquila et al. [125] and Zhang et al. [126] reported that X4 phenotype was more common among CCR5-Δ32 heterozygotes than among CCR5 wild-type homozygotes. The effect of CCR5 inhibitors on the virus phenotype has been analyzed in vitro and in vivo. Mosier et al. [127] reported that a CCR5-blocking CCL5 derivative induced appearance of X4 variants in hu-PBL-SCID mice infected with a R5 strain. In vitro, the CCR5 ligand CCL4 [128], the anti-CCR5 monoclonal antibody 2D7 [129], and a small CCR5 antagonist [130] induced the emergence of mutant resistant HIV-1 able to use CCR5 in the presence of the inhibitor, but unable to use CXCR4 as a coreceptor. Moreover, a study showing that macaques dual-infected with an R5 SIV and an X4 SHIV, and treated with a CCR5 inhibitor did not present with a sustained increase in X4 virus load might be reassuring [131]. In the above-mentioned MOTIVATE studies, the proportion of patients in the placebo group in whom therapy failed was more than twice the proportion observed in the maraviroc groups. However, at the time of failure, X4 viruses were detected in 57% of the nonresponders to maraviroc, and in only 6% of the nonresponders who received placebo [132]. Thus, CCR5 antagonists could induce the expansion of CXCR4-tropic strains, but from a preexisting pool rather than de novo [133,134]. Moreover, even in patients who failed to respond to maraviroc and developed X4 strains, a greater increase in the CD4 cell count was observed as compared with X4-positive nonresponders in the placebo group.

Thus, HIV-1 could escape from pressure exerted by CCR5 inhibitors by the expansion either of X4 variants or of R5 variants able to use CCR5 bound by the inhibitor [135]. The risk of shift from R5 to X4 consecutive to the administration of a CCR5 antagonist needs further investigation to be properly appreciated. Nonetheless, if X4 emergence correlates with an increase in CD4 T-cell loss, it is not definitively established that it is the presence of CXCR4-using strains that accelerates the progression rather than the worsening of the immunodeficiency that favors the viral switch. So the consequences of the appearance of X4 strains under treatment with CCR5 inhibitors is at present difficult to evaluate.

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Resistance to CCR5 antagonist

As for any other anti-HIV drug, there is a risk of natural or induced resistance to CCR5 inhibitors. This risk probably stems from the fact that there is some interstrain variability and plasticity in the way gp120 and CCR5 interact, as well as in the strength of this interaction. Actually, R5 envelopes with increased affinity for CCR5 [25,136,137], or displaying unusual binding sites on CCR5 [23,24,136–140] have been reported. Likewise, the anti-HIV potency of synthetic peptides to the first, second, or third extracellular loops of CCR5 has been shown to be variable among different R5 strains [141]. Repits et al. [142] have reported that during the course of the disease, R5 viruses evolve towards a lower sensitivity to inhibition by CCL5. Thus, it is predictable that R5 strains with an outstanding affinity for CCR5 and/or binding to an uncommon site on CCR5 exist naturally [143] and will emerge secondary to the selective pressure exerted by CCR5 antagonists [144]. A question is whether strains resistant to a CCR5 antagonist will [145] or will not [146] display reduced replication capacity.

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Immune consequences

Effects on specific immune responses

Because of the overlap between gp120 and C-C chemokine binding sites on CCR5, drugs blocking HIV binding may also block the binding of physiological ligands to CCR5. This side effect may have no consequence in physiological situations. But it might favor the development of infectious diseases in the course of which CCR5 plays a role, in as much as some of these infections are caused by agents such as C. neoformans, T. gondii, or herpes virus that are often encountered in HIV disease. In addition, infectious diseases as West Nile fever, not linked to HIV infection, might also be facilitated. A concern about the risk to up-regulate Epstein–Barr virus replication, and thereby to provoke the emergence of lymphomas was initially raised, but finally dropped [147]. Generally speaking no increase in the incidence of lymphoma has been so far observed [109,148]. Yet, these considerations might give an advantage to CCR5 targeting drugs that do not inhibit the binding of physiological ligands to CCR5. On the contrary, CCR5 blockers should have a beneficial effect on diseases in which CCR5 plays a detrimental role. This might be of interest in the future for HIV-infected patients with atherosclerosis.

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Effects on global immune activation and on T-cell apoptosis

Knowing the above-mentioned role of CCR5 in T-cell activation and the role of T-cell activation in HIV disease progression [149], it is tempting to speculate that CCR5, by facilitating the polyclonal stimulation of the cellular immune system, could facilitate T-cell destruction. In HIV-infected individuals, the triggering of cell surface CCR5 by soluble gp120 and/or by chemokines released by neighboring cells could increase CD4+ T-cell activation and apoptosis.

Many studies have shown that T-cell activation through CCR5 modulates programmed cell death. Some of these studies, but not all of them, have reported that CCR5 activation is proapoptotic [150,151]. If this is true, blocking CCR5 at the surface of CD4+ T cells from infected patients might reduce programmed cell death.

The hypothesis that CCR5, by promoting T-cell activation and apoptosis, could participate in T-cell destruction is supported by recent data from Ahuja's group. This group has shown that CCR5 genotype and CCL3 gene copy number are linked to disease progression independently of the level of viral replication [152]. This means that the CCL3, CCL4, CCL5/CCR5 axis could be involved in T-cell destruction through a mechanism not implicating the virus. Another study lends further credence to this idea. Pandrea et al. [153] have compared the level of CCR5 expression on the CD4+ T cells of primates that develop or not AIDS under SIV infection. Their result is striking: rhesus macaques, pigtail macaques, cynomolgus macaques, and baboons, who progress, overexpress CCR5, whereas sooty mangabeys, African green monkeys, sun-tailed monkeys, and mandrills who do not display high immune activation and who do not progress in spite of high viremia underexpress CCR5 [153]. Moreover, this hypothesis of an immunological responsibility of CCR5 in CD4+ T-cell destruction, apart from its virological responsibility as a coreceptor, could explain why patients treated with a CCR5 antagonist such as maraviroc present with an unusual rise in their CD4 cell counts [154,155]. Remarkably, this rise is not correlated with the antiviral effect [113], is observed even in patients harboring X4 strains [156], and comes with an increase in circulating CD8+ T cells. Additional studies will decipher whether this phenomenon is the consequence of a protective effect of CCR5 inhibitors on CD4+ and CD8+ T cells or of a change in T-cell homing.

Finally, if CCR5 inhibitors are actually capable of lowering global immune activation, they could be indicated in a situation when this phenomenon is harmful, immune reconstitution inflammatory syndrome.

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Alternatives to CCR5 antagonists

In addition to the administration of small molecules, antibodies or modified chemokines able to block CCR5, other approaches aiming at reducing CCR5 expression and/or function might be explored. They can be sorted into two categories.

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Extracellular approach

Induction of anti-CCR5 antibodies

Anti-CCR5 antibodies has been reported in normal individuals [157] (Fig. 4), particularly in individuals immunized with allogenic lymphocytes [158], and in seronegative partners of HIV-seropositive individuals [159], which may down-modulate surface CCR5 expression and block HIV-1 R5 infection. These observations suggest that the elicitation of such antibodies might induce an antiviral resistance. Yet, such a strategy would expose to the risk of autoimmunity. Moreover, by immunizing macaques against CCR5, Zuber et al. [160], although they elicited specific antibodies capable of neutralizing SIVsm strains in vitro, did not induce any protection of the vaccinated animals against SIV in-vivo infection.

Fig. 4

Fig. 4

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Induction of CCR5-binding chemokines

As CCR5-binding chemokines block HIV-1 R5 infection both by inducing CCR5 internalization and by competing with the virions for CCR5 binding, the up-regulation of these chemokines might be an alternative therapeutic strategy. Interestingly, allo-immunization increases the production of CCL3, CCL4, and CCL5, and results in partial resistance to HIV-1 R5 infection in vitro [161] and in vivo [162]. The search for biological situations or drugs able to increase the production of natural CCR5 ligands remains thus to be carried out. This is the case for instance of hydroxyurea, that arrests T-cell cycle in the late G1 phase, and thereby increases T-cell production of CCL-3, CCL-4, and CCL-5 [163].

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CCR5 heterodimerization and CCR5 heterodesensitization

Because CCR5 may heterodimerize with other GPCR, it is interesting to look for GPCR that might interfere with CCR5–HIV interplay through this heterodimerization. Thus, Rodriguez-Frade et al. [164] have reported the inhibition of HIV-1 R5 infection by an anti-CCR2 antibody that induced the oligomerization of CCR2 with CCR5. Another original approach might be to look for GPCR the stimulation of which might induce CCR5 internalization and/or desensitization. Thus, the stimulation of formyl peptide receptors with the bacterial peptide fMLF has been shown to result in protein kinase C-mediated serine phosphorylation and down-regulation of CCR5 [165]. The fact that CCR5 belongs to the largest family of receptors known so far that is in addition the most important drug target nowadays could open new therapeutic opportunities.

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Intracellular approach

Drugs inhibiting CCR5 production

A few drugs have been reported to be able to interfere with CCR5 gene expression (Fig. 5). For instance, rapamycin [166,167], a drug that disrupts IL-2 receptor signaling, prostaglandin E2, which increases intracellular concentration of cAMP [168], and statins [169] have been shown to lower CCR5 mRNA expression. Yet, rapamycin is an immunosuppressor and the administration of statin to HIV-infected persons has failed to reduce their viral load [170]. Likewise, thalidomide inhibits activation-induced CCR5 up-regulation at the surface of CD4+ T cells, probably by interfering with TNFα [171]. Moreover, the stability of CCR5 transcripts may be reduced by antioxidants [172]. Efficiency and side effects of these drugs remain to be evaluated.

Fig. 5

Fig. 5

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Transfer of genes interfering with CCR5 expression

In vitro, the transfer of genes coding for a reticulum-anchored CCR5-binding single-chain antibody [173] or C-C chemokine [174] has been shown to prevent cell surface expression of CCR5. Likewise, CCR5 mRNA may be destroyed by specific ribozyme [175] or small interfering RNA [176]. Yet, however promising these strategies are in vitro, their in-vivo application is restricted at present by the limitations of the tools for gene transfer we have at our disposal.

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Conclusion and perspectives

Targeting CCR5 in HIV infection is a new therapeutic approach which blocks a very early step of the virus cycle. Preliminary clinical experience with some CCR5 antagonists has been favorable. No toxic effect or drug resistance overlapping those of classical drugs has been observed. However, there remain questions to be addressed, including the risk of inducing an R5 to X4 switch, the risk of lowering some specific immune responses, the interactions with other antiretroviral agents, and long-term tolerability. Beyond the field of infectious diseases, the use of CCR5 antagonists will teach us more about chemokine receptors and will prepare the way for other therapeutic indications in diseases in which CCR5 is involved, as Th1-mediated autoimmune diseases or graft rejection.

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antiretroviral therapy; CCR5 receptor; CCR5 antagonists; CXCR4 receptor; chemokines; maraviroc

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