Skip Navigation LinksHome > September 24, 2009 - Volume 23 - Issue 15 > CCR5 antagonism in HIV infection: ways, effects, and side ef...
Text sizing:
A
A
A
AIDS:
doi: 10.1097/QAD.0b013e32832e71cd
Editorial Review

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

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

Free Access
Article Outline
Collapse Box

Author Information

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: j-reynes@chu-montpellier.fr

Back to Top | Article Outline

Introduction

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.

Back to Top | Article Outline

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
Image Tools
Back to Top | Article Outline

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.

Back to Top | Article Outline

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.

Back to Top | Article Outline

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
Image Tools

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.

Back to Top | Article Outline

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.

Back to Top | Article Outline
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].

Back to Top | Article Outline

CCR5 inhibitors

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

Back to Top | Article Outline
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].

Back to Top | Article Outline
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.

Back to Top | Article Outline
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].

Back to Top | Article Outline

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
Image Tools

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].

Back to Top | Article Outline
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.

Back to Top | Article Outline
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.

Back to Top | Article Outline
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.

Back to Top | Article Outline
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.

Back to Top | Article Outline

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.

Back to Top | Article Outline
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
Image Tools
Back to Top | Article Outline
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].

Back to Top | Article Outline
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.

Back to Top | Article Outline
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
Image Tools
Back to Top | Article Outline
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.

Back to Top | Article Outline

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.

Back to Top | Article Outline

References

1. Alkhatib G, Combadiere C, Broder CC, Feng Y, Kennedy PE, Murphy PM, et al. CC CKR5: a RANTES, MIP-1α, MIP-1β receptor as a fusion cofactor for macrophage-tropic HIV-1. Science 1996; 272:1955–1958.

2. Choe H, Farzan M, Sun Y, Sullivan N, Rollins B, Ponath PD, et al. The β-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell 1996; 85:1135–1148.

3. Deng H, Liu R, Ellmeier W, Choe S, Unumatz D, Burkhart M, et al. Identification of a major co-receptor for primary isolates of HIV-1. Nature 1996; 381:661–666.

4. Doranz BJ, Rucker J, Yi YJ, Smyth RJ, Samson M, Peiper SC, et al. A dual-tropic primary HIV-1 isolate that uses fusin and the beta-chemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors. Cell 1996; 85:1149–1158.

5. Dragic T, Litwin V, Allaway GP, Martin SR, Huang Y, Nagashima KA, et al. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature 1996; 381:667–673.

6. Samson M, Labbe O, Mollereau C, Vassart G, Parmentier M. Molecular cloning and functional expression of a new human CC-chemokine receptor gene. Biochemistry 1996; 35:3362–3367.

7. Blanpain C, Migeotte I, Lee B, Vakili J, Doranz BJ, Govaerts C, et al. CCR5 binds multiple CC-chemokines: MCP-3 acts as a natural antagonist. Blood 1999; 94:1899–1905.

8. Ogilvie P, Bardi G, Clark-Lewis I, Baggiolini M, Uguccioni M. Eotaxin is a natural antagonist for CCR2 and an agonist for CCR5. Blood 2001; 97:1920–1924.

9. Petkovic V, Moghini C, Paoletti S, Uguccioni M, Gerber B. I-TAC/CXCL11 is a natural antagonist for CCR5. J Leukoc Biol 2004; 76:701–708.

10. Cocchi F, De Vico AL, Garzino-Demo A, Arya SK, Gallo RC, Lusso P. Identification of RANTES, MIP-1α, and MIP-1β as the major HIV-suppressive factors produced by CD8+ T cells. Science 1995; 270:1811.

11. Feng Y, Broder CC, Kennedy PE, Berger EA. HIV-1 entry cofactor: functional cDNA cloning of a seven-transembrane, G protein-coupled receptor. Science 1996; 272:872–877.

12. Dean M, Carrington M, Winkler C, Huttley GA, Smith MW, Allikmets R, et al. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Science 1996; 273:1856–1862.

13. Liu R, Paxton WA, Choe S, Ceradini D, Martin SR, Horuk R, et al. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 1996; 86:367–377.

14. Michael NL, Moore JP. HIV-1 entry inhibitors: evading the issue. Nat Med 1999; 5:740–742.

15. Brumme ZL, Goodrich J, Mayer HB, Brumme CJ, Henrick BM, Wynhoven B, et al. Molecular and clinical epidemiology of CXCR4-using HIV-1 in a large population of antiretroviral-naïve individuals. J Infect Dis 2005; 192:466–474.

16. Richman DD, Bozzette SA. The impact of the syncitium-inducing phenotype of human immunodeficiency virus on disease progression. J Infect Dis 1994; 169:968–974.

17. Bou-HaR DC, Rderiquez G, Oravecz T, Berman PW, Lusso P, Norcross MA. Cryptic nature of envelope V3 region epitopes protects monocytotropic human immunodeficiency virus type 1 from antibody neutralization. J Virol 1994; 68:6006–6013.

18. Harouse JM, Buckner C, Gettie A, Fuller R, Bohm R, Blanchard J, et al. CD8+ T cell-mediated CXC chemokine receptor 4-simian/human immunodeficiency virus suppression in dually infected rhesus macaques. Proc Natl Acad Sci USA 2003; 100:10977–10982.

19. Xiao X, Wu L, Stantchev TS, Feng YR, Ugolini S, Chen H, et al. Constitutive cell surface association between CD4 and CCR5. Proc Natl Acad Sci USA 1999; 96:7496–7501.

20. Manes S, Mira F, Gomez-Mouton C, Lacalle RA, Keller P, Labrador JP, et al. Membrane raft microdomain mediate front-rear polarity in migrating cells. EMBO J 1999; 18:6211–6220.

21. Doranz BJ, Baik SS, Doms RW. Use of a gp120 binding assay to dissect the requirements and kinetics of human immunodeficiency virus fusion events. J Virol 1999; 73:10346–10358.

22. Glushakova S, Baibakov B, Margolis LB, Zimmerberg J. Infection of human tonsil histocultures: a model for HIV pathogenesis. Nat Med 1995; 1:1320–1322.

23. Rabut GEE, Konner JA, Kajumo F, Moore JP, Dragic T. Alanine substitutions of polar and nonpolar residues in the amino-terminal domain of CCR5 differently impair entry of macrophage- and dualtropic isolates of human immunodeficiency virus type 1. J Virol 1998; 72:3464–3468.

24. Thompson DAD, Cormier EG, Dragic T. CCR5 and CXCR4 usage by nonclade B human immunodeficiency virus type 1 primary isolates. J Virol 2002; 76:3059–3064.

25. Kuhmann SE, Platt EJ, Kozak SL, Kabat D. Cooperation of multiple CCR5 coreceptors is required for infections by human immunodeficiency virus type 1. J Virol 2000; 74:7005–7015.

26. Rottman JB, Ganley KP, Williams K, Wu L, Mackay CR, Ringler DJ. Cellular localization of the chemokine receptor CCR5. Correlation to cellular target HIV-1 infection. Am J Pathol 1997; 151:1341–1351.

27. Bleul CC, Su L, Hoxie JA, Springer TA, Mackay R. The HIV coreceptors CXCR4 and CCR5 are differentially expressed and regulated on human T lymphocytes. Proc Natl Acad Sci USA 1997; 94:1925–1930.

28. Lee B, Sharron M, Montaner LJ, Weissman D, Doms RW. Quantification of CD4, CCR5, and CXCR4 levels on lymphocyte subsets, dendritic cells, and differentially conditioned monocyte-derived macrophages. Proc Natl Acad Sci USA 1999; 96:5215–5220.

29. Loetscher P, Uguccioni M, Bordoli L, Baggiolini M, Moser B, Chizzolini C, et al. CCR5 is characteristic of TH1 lymphocytes. Nature 1998; 391:344–345.

30. Reynes J, Portales P, Segondy M, Baillat V, André P, et al. CD4+ T cell surface CCR5 density and virus load in persons infected with human immunodeficiency virus type 1. J Infect Dis 2000; 182:1285–1286.

31. Martin MP, Dean M, Smith MW, Winkler C, Gerrard B, Michael NL, et al. Genetic acceleration of AIDS progression by a promoter variant of CCR5. Science 1998; 282:1907–1911.

32. McDermott DH, Zimmereman PA, Guignard F, Kleeberger CA, Leitman SF, the Multicenter AIDS Cohort Study (MACS). CCR5 promoter polymorphism and HIV-1 disease progression. Lancet 1998; 352:866–870.

33. Mummidi S, Ahuja SS, Gonzalez E, Anderson SA, Santiago EN, Stephan KT, et al. Genealogy of the CCR5 locus and chemokine system gene variants associated with altered rates of HIV-1 disease progression. Nature Med 1998; 4:786–793.

34. Mueller A, Kelly E, Strange PG. Pathways for internalization and recycling of the chemokine receptor CCR5. Blood 2002; 99:785–791.

35. Signoret N, Pelchen-Matthews A, Mack M, Proudfoot AE, Marsh M. Endocytosis and recycling of the HIV coreceptor CCR5. J Cell Biol 2000; 151:1281–1294.

36. Lin YL, Mettling C, Portalès P, Rouzier R, Clot J, Reynes J, et al. The chemokine CCL5 regulates the in vivo cell surface expression of its receptor, CCR5. AIDS 2008; 22:430–432.

37. Venkatesan R, Rose JJ, Lodge R, Murphy PM, Foley JF. Distinct mechanisms of agonist-induced endocytosis for human chemokine receptors CCR5 and CXCR4. Mol Biol Cell 2003; 14:3305–3324.

38. Singer I, Scott S, Kawka DW, Chin J, Daughery BL, DeMartino JA, et al. CCR5, CXCR4, and CD4 are clustered and closely apposed on microvilli of human macrophages and T cells. J Virol 2001; 75:3779–3790.

39. Steffens CM, Hope TJ. Localization of CD4 and CCR5 in living cells. J Virol 2003; 77:4985–4991.

40. Issafras H, Angers S, Bulenger S, Blanpain C, Parmentier M, Labbe-Julie C, et al. Constitutive agonist-independent CCR5 oligomerization and antibody-mediated clustering occuring at physiological levels of receptors. J Biol Chem 2002; 277:34666–34673.

41. Benkirane M, Willey R, Jin D-Y, Chun RF, Koup RA, Jeang K-T. Mechanism of transdominant inhibition of CCR5-mediated HIV-1 infection by CCR5Δ32. J Biol Chem 1997; 272:30603–30606.

42. Mellado M, Rodriguez-Frade JM, Vila-Coro AJ, de Ana AM, Martinez-A C. Chemokine control of HIV-1 infection. Nature 1999; 400:723–724.

43. Suzuki S, Chuang LF, Yau P, Doi RH, Chuang RY. Interactions of opioid and chemokine receptors: oligomerization of mu, kappa, and delta with CCR5 on immune cells. Exp Cell Res 2002; 280:192–200.

44. Ebert LM, McColl SR. Up-regulation of CCR5 and CCR6 on distinct subpopulations of antigen-activated CD4+ T lymphocytes. J Immunol 2002; 168:65–72.

45. Carroll RG, Riley JL, Levine BL, Feng Y, Kaushal S, Ritchey DW, et al. Differential regulation of HIV-1 fusion cofactor expression by CD28 costimulation of CD4+ T cells. Science 1997; 276:273–276.

46. Kinter A, Arthos J, Cicala C, Fauci AS. Chemokines, cytokines and HIV: a complex network of interactions that influence HIV pathogenesis. Immunol Rev 2000; 177:88–98.

47. Vassiliadou N, Tucker L, Anderson DJ. Progesterone-induced inhibition of chemokine receptor expression on peripheral blood mononuclear cells correlates with reduced HIV-1 infectability in vitro. J Immunol 1999; 162:7510–7518.

48. Anton PA, Elliott J, Poles MA, McGowan IM, Matud J, Hultin LE, et al. Enhanced levels of functional HIV-1 co-receptors on human mucosal T cells demonstrated using intestinal biopsy tissue. AIDS 2000; 14:1761–1765.

49. Brenchley JM, Schacker TW, Ruff LE, Price DA, Taylor JH, Beilman GJ, et al. CD4+ T cell depletion during all stages of HIV disease occurred predominantly in the gastrointestinal tract. J Exp Med 2004; 200:749–759.

50. Lillard JW Jr, Boyaka PN, Taub DD, McGhee JR. RANTES potentiates antigen-specific mucosal immune responses. J Immunol 2001; 166:162–169.

51. Appay V, Dunbar PR, Cerundolo V, McMichael A, Czaplewski L, Rowland-Jones S. RANTES activates antigen-specific cytotoxic T lymphocytes in a mitogen-like manner through cell surface aggregation. Int Immunol 2000; 12:1173–1182.

52. Bacon KB, Premack BA, Gardner P, Schall TJ. Activation of dual T cell signaling pathways by the chemokine RANTES. Science 1995; 269:1727–1730.

53. Taub DD, Turkovski-Corrales SM, Key ML, Longo DL, Murphy WJ. Chemokines and T lymphocyte activation: I Beta chemokines costimulate human T lymphocyte activation in vitro. J Immunol 1996; 156:2095–2103.

54. Contento RL, Molon B, Boularan C, Pozzan T, Manes S, Mariullo S, et al. CXCR4-CCR5: a couple modulating T cell functions. Proc Natl Acad Sci USA 2008; 105:10101–10106.

55. Castellino F, Huang AY, Altan-Bonnet G, Stoll S, Scheineker C, Germain RN. Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell-dendritic cell interaction. Nature 2006; 440:890–895.

56. Hugues S, Scholer A, Boissonnas A, Nussbaum A, Combadière C, Amigorena S, et al. Dynamic imaging of chemokine-dependent CD8+ T cell help for CD8+ T cell responses. Nat Immunol 2007; 8:921–930.

57. Patterson BK, Czerniewski M, Andersson J, Sullivan Y, Su F, Jiyamapa D, et al. Regulation of CCR5 and CXCR4 expression by type 1 and 2 cytokines: CCR5 expression is downregulated by IL-10 in CD4-positive lymphocytes. Clin Immunol 1999; 91:254–262.

58. Schrum S, Probst P, Fleischer B, Zipfel PF. Synthesis of the CC-chemokines MIP-1alpha, MIP-1beta, and RANTES is associated with a type 1 immune response. J Immunol 1996; 157:3598–3604.

59. Zou W, Borvak J, Marches F, Wei S, Galanaud P, Emilie D, et al. Macrophage-derived dendritic cells have strong Th1-polarizing potential mediated by beta-chemokines rather than IL-12. J Immunol 2000; 165:4388–4396.

60. Dorner BG, Scheffold A, Rolph MS, Huser BG, Kaufmann SH, Radbruch A, et al. MIP-1alpha, MIP-1beta, RANTES, and ATAC/lymphotactin function together with IFN-gamma as type 1 cytokines. Proc Natl Acad Sci USA 2002; 99:6181–6186.

61. Andres PG, Beck PL, Mizoguchi E, Mitzoguchi A, Bhan AK, Dawson TC, et al. Mice with a selective deletion of the CC chemokine receptors 5 or 2 are protected from dextran sulfate-mediated colitis: lack of CC chemokine receptor 5 expression results in a NK1.1+ lymphocyte-associated Th2-type immune response in the intestine. J Immunol 2000; 164:6303–6312.

62. Zhou Y, Kurihara T, Ryseck R-P, Yang Y, Ryan C, Loy J, et al. Impaired macrophage function and enhanced T-cell dependent immune response in mice lacking CCR5, the mouse homologue of the major HIV-1 coreceptor. J Immunol 1998; 160:4018–4025.

63. Nguyën GT, Carrington M, Beeler JA, Dean M, Aledort LM, Blatt PM, et al. Phenotypic expressions of CCR5-Δ32/Δ32 homozygosity. J Acquir Immune Defic Syndr 1999; 22:75–82.

64. Mettimano M, Specchia ML, Ianni A, Arzani D, Ricciardi G, Savi L, et al. CCR5 and CCR2 gene polymorphisms in hypertensive patients. Br J Biomed Sci 2003; 60:19–21.

65. Zlotnik A, Yoshie O. Chemokines: a new classification system and their role in immunity. Immunity 2000; 12:121–127.

66. Floto RA, MacAry PA, Boname JM, Mien TS, Kampmann B, Hair JR, et al. Dendritic cell stimulation by mycobacterial Hsp70 is mediated through CCR5. Science 2006; 314:454–458.

67. Aliberti J, Valenzuela JG, Carruthers VB, Hieny S, Andersen J, Charest H, et al. Molecular mimicry of a CCR5 binding-domain in the microbial activation of dendritic cells. Nat Immunol 2003; 4:485–490.

68. Rahbar R, Murooka TT, Huinek AA, Galligan CL, Sassano A, Yu C, et al. Vaccinia virus activation of CCR5 invokes tyrosine phosphorylation signaling events that support virus replication. J Virol 2006; 80:7245–7259.

69. Huffnagel GB, McNeil LK, McDonald RA, Murphy JW, Toews GB, Maeda N, et al. Role of C-C chemokine receptor 5 in organ-specific and innate immunity to Cryptococcus neoformans. J Immunol 1999; 163:4642–4646.

70. Luangsay S, Kasper LH, Rachinel N, Minns LA, Mennechet FJ, Vandewalle A, et al. CCR5 mediates specific migration of Toxoplasma gondii-primed CD8 lymphocytes to inflammatory intestinal epithelial cells. Gastroenterology 2003; 125:491–500.

71. Dawson TC, Beck MA, Kuziel WA, Henderson F, Maeda N. Contrasting effects of CCR5 and CCR2 deficiency in the pulmonary inflammatory response to influenza A virus. Am J Pathol 2000; 156:1951–1959.

72. Thapa M, Kuziel WA, Carr DJJ. Susceptibility of CCR5-deficient mice to genital herpes simplex virus type 2 is linked to NK cell mobilization. J Virol 2007; 81:3704–3713.

73. Machado FS, Koyama NS, Carregaro V, Ferreira BR, Milanezi CM, Teixeira MM, et al. CCR5 plays a critical role in the development of myocarditis and host protection in mice infected with Trypanosoma cruzi. J Infect Dis 2005; 4:627–636.

74. Barr EL, Ouburg S, Igietseme JU, Morré SA, Okwandu E, Eko FO, et al. Host inflammatory response and development of complications of Chlamydia trachomatis genital infection in CCR5-deficient mice and subfertile women with the CCR5delta32 gene deletion. J Microbiol Immunol Infect 2005; 38:244–254.

75. Hull J, Rowlands K, Lockhart E, Moore C, Sharland M, Kwiatkowski D. Variants of the chemokine CCR5 are associated with severe bronchiolitis caused by respiratory syncytial virus. J Infect Dis 2003; 188:904–907.

76. Glass WG, McDermott DH, Lim JK, Lekhong S, Yu SF, Frank WA, et al. CCR5 deficiency increases risk of symptomatic West Nile virus infection. J Exp Med 2006; 203:35–40.

77. Kindberg E, Mickiene A, Ax C, Akerlind B, Vene S, Lindquist L, et al. A deletion in the chemokine receptor 5 (CCR5) gene is associated with tickborne encephalitis. J Infect Dis 2008; 197:266–269.

78. Woitas RP, Ahlenstiel G, Iwan A, Rockstroh JK, Brackmann HH, Kupfer B, et al. Frequency of the HIV-protective CC chemokine receptor 5-Δ32/Δ32 phenotype is increased in hepatitis C. Gastroenterology 2002; 122:1721–1728.

79. Ahlenstiel G, Berg T, Woitas RP, Grunhage F, Iwan A, Hess L, et al. Effects of the CCR5-Δ32 mutation on antiviral treatment in chronic hepatitis. J Hepatol 2003; 39:245–252.

80. Klein RS. Discussion on frequency of the HIV-protective CC chemokine receptor 5-Δ32/Δ32 genotype is increased in hepatitis C. Gastroenterology 2003; 124:1558.

81. Mangia A, Santoro R, D'agruma L, Andriulli A. HCV chronic infection and CCR5-Δ32/Δ 32. Gastroenterology 2003; 124:868–869.

82. Poljak M, Seme K, Marin IJ, Babic DZ, Matcic M, Meglic J. Frequency of the 32-base pair deletion in the chemokine receptor CCR5 gene is not increased in hepatitis C patients. Gastroenterology 2003; 124:1558–1560.

83. Promrat K, McDermott DH, Gonzalez CM, Kleiner DE, Koziol DE, Lessie M, et al. Associations of chemokine system polymorphisms with clinical outcomes and treatment responses of chronic hepatitis C. Gastroenterology 2003; 124:352–360.

84. Zhang M, Goedert JJ, O'Brien TR. High frequency of CCR5-Δ32 homozygosity in HCV-infected, HIV-1-uninfected hemophiliacs results from resistance to HIV-1. Gastroenterology 2003; 124:867–868.

85. Belnoue E, Kayibanda M, Deschemin JC, Viguier M, Mack M, Kuziel WA, et al. CCR5 deficiency decreases susceptibility to experimental cerebral malaria. Blood 2003; 101:4253–4259.

86. Glass WG, Liu MT, Kuziel WA, Lane TE. Reduced macrophage infiltration and demyelination in mice lacking the chemokine receptor CCR5 following infection with a neurotropic coronavirus. Virology 2001; 288:8–17.

87. Moreira AP, Cavassani KA, Massafera Tristao FS, Campanelli AP, Martinez R, Rossi MA, et al. CCR5-dependent regulatory T cell migration mediates fungal survival and severe immunosuppression. J Immunol 2008; 180:3049–3056.

88. Cooke SP, Forrest G, Venables PJW, Hajeer A. The Δ32 deletion of CCR5 receptor in rheumatoid arthritis. Arthritis Rheumatol 1998; 41:1135–1136.

89. Gomez-Reino JJ, Pablos JL, Carreira PE, Santiago B, Serrano L, Vicario JL, et al. Association of rheumatoid arthritis with a functional chemokine receptor, CCR5. Arthritis Rheum 1999; 42:989–992.

90. Zapico I, Coto E, Rodriguez A, Alvarez C, Torre JC, Alvarez V. CCR5 (chemokine receptor-5) DNA-polymorphism influences the severity of rheumatoid arthritis. Genes Immun 2000; 1:288–289.

91. Garred P, Madsen HO, Petersen J, Marquart H, Hansen TM, Sorensen SF, et al. CC chemokine receptor 5 polymorphism in rheumatoid arthritis. J Rheumatol 1998; 25:1462–1465.

92. Quinone MP, Martinez HG, Jimenez F, Estrada CA, Dudley M, Willmon O, et al. CC ckemokine receptor 5 influences late stage atherosclerosis. Atherosclerosis 2007; 195:e92–e103.

93. Zernecke A, Liehn EA, Gao JL, Kuziel WA, Murphy PM, Weber C. Deficiency in CCR5 but not CCR1 protects against neointima formation in atherosclerosis-prone mice: involvement of IL-10. Blood 2006; 107:4240–4243.

94. Veillard NR, Kwak B, Pelli G, Mulhaupt F, James RW, Proudfoot AE, et al. Antagonism of RANTES receptors reduces atherosclerotic plaque formation in mice. Circ Res 2004; 94:253–261.

95. Fischereder M, Luckow B, Hocher B, Wüthrich RP, Rothenpieler U, Schneeberger H, et al. CC chemokine receptor 5 and renal-transplant survival. Lancet 2001; 357:1758–1761.

96. Abdi R, Tran TB, Sahagun-Ruiz A, Murphy PM, Brenner BM, Milford EL, et al. Chemokine receptor polymorphism and risk of acute rejection in human renal transplantation. J Am Soc Nephrol 2002; 13:754–758.

97. Schröder C, Pierson RNr, Nguyen BN, Kawka DW, Peterson LB, Wu G, et al. CCR5 blockade modulates inflammation and alloimmunity in primates. J Immunol 2007; 179:2289–2299.

98. Hall IP, Wheatley A, Christie G, McDougall C, Hubbard R, Helms PJ. Association of CCR5 Δ32 with reduced risk of asthma. Lancet 1999; 354:1264–1265.

99. Mitchell TJ, Walley AJ, Pease JE, Venables PJW, Wiltshire S, Williams TJ, et al. Delta32 deletion of CCR5 gene and association with asthma or atopy. Lancet 2000; 356:1491–1492.

100. Nagy A, Kozma GT, Bojszko A, Krikovszky D, Falus A, Szalai C. No association between asthma or allergy and the CCR5Delta 32 mutation. Arch Dis Child 2002; 86:426.

101. Sandford AJ, Zhu S, Bai TR, Fitzgerald JM, Pare PD. The role of the C-C chemokine receptor-5 Delta32 polymorphism in asthma and in the production of regulated on activation, normal T cells expressed and secreted. J Allergy Clin Immunol 2001; 108:69–73.

102. Lenzsch S, Gries M, Janz M, Bargou R, Dörken B, Mapara MY. Macrophage inflammatory protein 1-alpha (MIP-1α) triggers migration and signaling cascades mediating survival and proliferation in multiple myeloma (MM) cells. Blood 2003; 101:3568–3573.

103. Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, et al. Mesenchymal stem cells within tumor stroma promote breast cancer metastasis. Nature 2007; 449:557–563.

104. Lavergne E, Combadière C, Iga M, Boissonnas A, Bonduelle O, Maho M, et al. Intratumoral CC chemokine ligand 5 overexpression delays tumor growth and increases tumor infiltration. J Immunol 2004; 173:3755–3762.

105. Mañes S, Mira E, Colomer R, Montero S, Real LM, Gómez-Moutón C, et al. CCR5 expression influences the progression of human cancer in a p53-dependent manner. J Exp Med 2003; 198:1381–1389.

106. Castonguay LA, Weng Y, Adolfsen W, Di Salvo J, Kilburn R, Caldwell CG, et al. Binding of 2-aryl-4-(piperidin-1-yl)butanamines and 1,3, 4-trisubstituted pyrrolidines to human CCR5: a molecular modeling-guided mutagenesis study of the binding pocket. Biochemistry 2003; 42:1544–1550.

107. Tsamis F, Gavrilov S, Kajumo F, Seibert C, Kuhmann S, Ketasz T, et al. Analysis of the mechanism by which the small-molecule CCR5 antagonists SCH-351125 and SCH-350581 inhibit human immunodeficiency virus type 1 entry. J Virol 2003; 77:5201–5208.

108. Muniz-Medina VM, Jones S, Maglich JM, Galardi C, Hollingsworth RE, Kazmierski WM, et al. The relative activity of ‘function sparing’ HIV-1 entry inhibitors on viral entry and CCR5 internalization: is allosteric functional selectivity a valuable therapeutic property? Mol Pharmacol 2008; 75:490–501.

109. Gulick RM, Lalezari J, Goodrich J, Clumeck N, DeJesus E, Horban A, et al. Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med 2008; 359:1429–1441.

110. Nichols WG, Steel HM, Bonny T, Adkinson K, Curtis L, Millard J, et al. Hepatotoxicity observed in clinical trials of aplaviroc (GW873140). Antimicrob Agents Chemother 2008; 52:858–865.

111. Esté JA, Telenti A. HIV entry inhibitors. Lancet 2007; 370:81–88.

112. Jacobson JM, Saag MS, Thompson MA, Fischl MA, Liporace R, Reichman RC, et al. Antiviral activity of single-dose PRO 140, a CCR5 monoclonal antibody, in HIV-infected adults. J Infect Dis 2008; 198:1345–1352.

113. Lalezari J, Yadavalli GK, Para M, Richmond G, DeJesus E, Brown SJ, et al. Safety, pharmacokinetics, and antiviral activity of HGS004, a novel fully human IgG4 monoclonal antibody against CCR5, in HIV-1-infected patients. J Infect Dis 2008; 197:721–727.

114. Cairns JS, D'Souza MP. Chemokines and HIV-1 s receptors: the therapeutic connection. Nat Med 1998; 4:563–568.

115. Gaertner H, Cerini F, Escola JM, Kuenzi G, Melotti A, Offord R, et al. Highly potent, fully recombinant anti-HIV chemokines: reengineering a low-cost microbicide. Proc Natl Acad Sci USA 2008; 105:17706–17711.

116. Lelièvre J-D, Petit F, Perrin L, Mammano F, Arnoult D, Ameisen JC, et al. The density of coreceptors at the surface of CD4+ T cells contributes to the extent of human immunodeficiency virus type 1 viral replication-mediated T cell death. AIDS Res Hum Retroviruses 2004; 20:1230–1243.

117. Madani N, Hubicki AM, Perdigoto AL, Springer M, Sodroski J. Inhibition of human immunodeficiency virus envelope glycoprotein-mediated single cell lysis by low-molecular-weight antagonists of viral entry. J Virol 2007; 81:532–538.

118. Tremblay CL, Giguel F, Kollmann C, Guan Y, Chou TC, Baroudy BM, et al. Anti-human immunodeficiency virus interactions of SCH-C (SCH 351125), a CCR5 antagonist, with other antiretroviral agents in vitro. Antimicrob Agents Chemother 2002; 46:1336–1339.

119. Gervaix A, Nicolas J, Portales P, Posfay-Barbe K, Wyler CA, Segondy M, et al. Response to treatment and disease progression linked to CD4+ T cell surface CCR5 density in HIV-1 vertical infection. J Infect Dis 2002; 185:1055–1061.

120. Vincent T, Portales P, Baillat V, Eden A, Clot J, Reynes J, et al. The immunological response to highly active antiretroviral therapy is linked to CD4+ T-cell surface CCR5 density. J Acquir Immune Defic Syndr 2006; 43:377–378.

121. Reeves JD, Gallo SA, Ahmad N, Miamidian JL, Harvey PE, Sharron M, et al. Sensitivity of HIV-1 to entry inhibitors correlates with envelope/coreceptor affinity, receptor density, and fusion kinetics. Proc Natl Acad Sci USA 2002; 99:16249–16254.

122. Heredia A, Gilliam B, DeVico A, Le N, Bamba D, Flinko R, et al. CCR5 density levels on primary CD4 T cells impact the replication and enfuvirtide susceptibility of R5 HIV-1. AIDS 2007; 21:1317–1322.

123. Agrawal L, Lu X, Qingwen J, VanHorn-Ali Z, Nicolescu IV, McDermott DH, et al. Role of CCR5Δ32 protein in resistance to R5, R5X4, and X4 human immunodeficiency virus type 1 in primary CD4+ cells. J Virol 2004; 78:2277–2287.

124. de Roda Husman A-M, Koot M, Cornelissen M, Keet IP, Brouwer M, Broersen SM, et al. Association between CCR5 genotype and the clinical course of HIV-1 infection. Ann Intern Med 1997; 127:882–890.

125. D'aquila RT, Sutton L, Savars A, Hughes MD, Johnson VA. CCR5/delta(ccr5) heterozygosity: a selective pressure for the syncitium-inducing human immunodeficiency virus type 1 phenotype. J Infect Dis 1998; 177:1549–1553.

126. Zhang L, He T, Huang Y, Chen Z, Guo Y, Wu S, et al. Chemokine receptor usage by diverse primary isolates of human immunodeficiency virus type 1. J Virol 1998; 72:9307–9312.

127. Mosier DE, Picchio GR, Gulizia RJ, Sabbe R, Poignard P, Picard L, et al. Highly potent RANTES analogues either prevent CCR5-using HIV-1 infection in vivo or rapidly select for CXCR4-using variants. J Virol 1999; 73:3544–3550.

128. Maeda Y, Foda M, Matsushita S, Harada S. Involvement of both the V2 and V3 regions of the CCR5-tropic human immunodeficiency virus type 1 envelope in reduced sensitivity to macrophage inflammatory protein 1alpha. J Virol 2000; 74:1787–1793.

129. Aarons EJ, Beddows S, Willingham T, Wu L, Koup RA. Adaptation to blockade of human immunodeficiency virus type 1 entry imposed by the anti-CCR5 monoclonal antibody 2D7. Virology 2001; 287:382–390.

130. Trkola A, Kuhmann SE, Strizki JM, Maxwell E, Ketas T, Morgan T, et al. HIV-1 escape from a small molecule, CCR5-specific entry inhibitor does not involve CXCR4 use. Proc Natl Acad Sci USA 2002; 99:395–400.

131. Wolinsky SM, Veazy RS, Kunstman KJ, Klasse PJ, Dufour J, Marozsan AJ, et al. Effect of a CCR5 inhibitor on viral loads in macaques dual-infected with R5 and X4 primate immunodeficiency viruses. Virology 2004; 328:19–29.

132. Fätkenheuer G, Nelson M, Lazzarin A, Konourina I, Hoepelman AI, Lampiris H, et al. Subgroup analyses of maraviroc in previously treated R5 HIV-1 infection. N Engl J Med 2008; 359:1442–1455.

133. Lewis ME, Van der Ryst E, Youle M, Youle M, Jenkins T, James I, et al. Phylogenetic analysis and co-receptor tropism of HIV-1 envelope sequences from patients with emergence of CXCR4 using virus following treatment with the CCR5 antagonist UK-427,857. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy; Washington [Late-Breaker Abstract H-548b] 2004.

134. Westby M, Lewis M, Withcomb J, Youle M, Pozniak AL, James IT, et al. Emergence of CXCR4-using human immunodeficiency virus type 1 (HIV-1) variants in a minority of HIV-1-infected patients following treatment with the CCR5 antagonist maraviroc is from a pretreatment CXCR4-using virus reservoir. J Virol 2006; 80:4909–4920.

135. Westby M, Smith-Burchnell C, Mori J, Lewis M, Mosley M, Stockdale M, et al. Reduced maximal inhibition in phenotypic susceptibility assays indicates that viral strains resistant to the CCR5 antagonist maraviroc utilize inhibitor-bound receptor for entry. J Virol 2007; 81:2359–2371.

136. Boyd MT, Simpson GR, Cann AJ, Johnson MA, Weiss RA. A single amino acid substitution in the V1 loop of human immunodeficiency virus type 1gp120 alters cellular tropism. J Virol 1993; 67:3649–3652.

137. Dejucq N, Simmons G, Clapham PR. Expanded tropism of primary human immunodeficiency virus type 1 R5 strains to CD4(+) T-cell lines determined by their capacity to exploit low concentrations of CCR5. J Virol 1999; 73:7842–7847.

138. Bieniasz PD, Fridell RA, Aramori I, Ferguson SSG, Caron MG, Cullen BR. HIV-1-induced cell fusion is mediated by multiple regions within both the viral envelope and the CCR-5 co-receptor. EMBO J 1997; 16:2599–2609.

139. Edinger AL, Amedee A, Miller K, Doranz BJ, Endres M, Sharron M, et al. Differential utilization of CCR5 by macrophage and T cell tropic Simian Immunodeficiency Virus strains. Proc Natl Acad Sci USA 1997; 94:4005–4010.

140. Rucker J, Samson M, Doranz BJ, Libert F, Berson JF, Yi Y, et al. Regions on β-chemokine receptors CCR5 and CCR2b that determine HIV-1 corfactor specificity. Cell 1996; 87:437–446.

141. Agrawal L, VanHorm-Ali Z, Berger EA, Alkhatib G. Specific inhibition of HIV-1 coreceptor activity by synthetic peptides corresponding to the predicted extracellular loops of CCR5. Blood 2004; 103:1211–1217.

142. Repits J, Fenyö EM, Jansson M. Studies on the evolution of receptor use by HIV-1 R5 viruses isolated from AIDS patients. XV International AIDS Conference; 2004 [Abstract TuPeA4326].

143. Soulié C, Malet I, Lambert-Niclot S, Tubiana R, Thévenin M, Simon A, et al. Primary genotypic resistance of HIV-1 to CCR5 antagonists in CCR5 antagonist treatment-naive patients. AIDS 2008; 22:2212–2214.

144. Tsibris AM, Sagar M, Gulick RM, Su Z, Hughes M, Greaves W, et al. In vivo emergence of vicriviroc resistance in a human immunodeficiency virus type 1 subtype C-infected subject. J Virol 2008; 82:8210–8214.

145. Riley J, Huang W, Wojcik L, Xu S, Kuhmann S, Moore JP, et al. HIV resistance to CCR5 antagonists requires multiple mutations and is associated with reduced replication capacity. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy; Washington [Abstract H-192] 2004.

146. Anastassopoulou CG, Marozsan AJ, Matet A, Snyder AD, Arts EJ, Kuhmann SE, et al. Escape of HIV-1 from a small molecule CCR5 inhibitor is not associated with a fitness loss. PLoS Pathog 2007; 3:e79.

147. Tsibris AM, Paredes R, Chadburn A, Su Z, Henrich TJ, Krambrink A, et al. Lymphoma diagnosis and plasma Epstein-Barr virus load during vicriviroc therapy: results of the AIDS Clinical Trials Group A5211. Clin Infect Dis 2009; 48:642–649.

148. Landovitz RJ, Angel JB, Hoffmann C, Horst H, Opravil M, Long J, et al. Phase II study of vicriviroc versus efavirenz (both with zidovudine/lamivudine) in treatment-naive subjects with HIV-1 infection. J Infect Dis 2008; 198:1112–1122.

149. Giorgi JV, Hultin LE, McKeating JA, Johnson TD, Owens B, Jacobson LP, et al. Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage. J Infect Dis 1999; 179:859–870.

150. Cartier C, Dubois-Dauphin M, Hartley O, Irminger-Finger I, Krause KH. Chemokine-induced cell death in CCR5-expressing neuroblastoma cells. Neuroimmunol 2003; 145:27–39.

151. Murooka TT, Wong MM, Rahbar R, Majchrzak-Kita B, Proudfoot AE, Fish EN. CCL5-CCR5-mediated apoptosis in T cells: requirement for glycosaminoglycan binding and CCL5 aggregation. J Biol Chem 2006; 281:25184–25194.

152. Dolan MJ, Kulkarni H, Camargo JF, He W, Smith A, Anaya JM, et al. CCL3L1 and CCR5 influence cell-mediated immunity and affect HIV-AIDS pathogenesis via viral entry-independent mechanisms. Nat Immunol 2007; 8:1324–1336.

153. Pandrea I, Apetrei C, Gordon S, Barbercheck J, Dufour J, Bohm R, et al. Paucity of CD4+CCR5+ T cells is a typical feature of natural SIV hosts. Blood 2007; 109:1069–1076.

154. Saag M, Ive P, Heera J, Tawadrous M, DeJesus E, Clumeck N, et al. A multicenter, randomized, double-blind, comparative trial of a novel CCR5 antagonist, maraviroc versus efavirenz, both in combination with combivir (zidovudine/lamivudine), for the treatment of antiretroviral-naive subjects infected with R5 HIV 1: week 48 results of the MERIT study. 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention; Sydney; 2007 [Abst. WESS104].

155. Wilkin T, Ribaudo H, Gulick R. The relationship of CCR5 inhibitors to CD4 count changes: a meta-analysis of recent clinical trials in treatment-experienced subjects. 15th Conference on Retroviruses and Opportunistic Infections; Boston; 2008 [Abst.800].

156. Gulick RM, Su Z, Flexner C, Hughes MD, Skolnik PR, Wilkin TJ, et al. Phase 2 study of the safety and efficacy of vicriviroc, a CCR5 inhibitor, in HIV-1-infected, treatment-experienced patients: AIDS clinical trials group 5211. J Infect Dis 2007; 196:304–312.

157. Bouhlal H, Hocini H, Quillent-Gregoire C, Donkova V, Rose S, Amara A, et al. Antibodies to C-C chemokine receptor 5 in normal human IgG block infection of macrophages and lymphocytes with primary R5-tropic strains of HIV-1. J Immunol 2001; 166:7606–7611.

158. Greene E, Pinto LA, Kwak-Kim JY, Giorgi JV, Landay AL, Kessler HA, et al. Increased levels of anti-CCR5 antibodies in sera from individuals immunized with allogenic lymphocytes. AIDS 2000; 14:2627–2628.

159. Lopalco L, Barassi C, Pastori C, Longhi R, Burastero SE, Tambussi G, et al. CCR5-reactive antibodies in seronegative partners of HIV-seropositive individuals down-modulate surface CCR5 in vivo and neutralize the infectivity of R5 strains of HIV-1 in vitro. J Immunol 2000; 164:3426–3433.

160. Zuber B, Hinkula J, Vodros D, Lundholm P, Nilsson C, Morner A, et al. Induction of immune responses and break of tolerance by DNA against the HIV-1 coreceptor CCR5 but no protection from SIVsm challenge. Virology 2000; 278:400–411.

161. Wang Y, Tao L, Mitchell E, Bravery C, Berlingieri P, Armstrong P, et al. Allo-immunization elicits CD8+ T cell-derived chemokines. HIV suppressor factors and resistance to HIV infection in women. Nat Med 1999; 5:1004–1009.

162. Lehner T, Wang L, Cranage M, Tao L, Mitchell E, Bravery C, et al. Up-regulation of β-chemokines and down-modulation of CCR5 co-receptors inhibit simian immunodeficiency virus transmission in nonhuman primates. Immunology 2000; 99:569–577.

163. Heredia A, Davis C, Amoroso A, Dominique JK, Le N, Klingebiel E, et al. Induction of G1 cycle arrest in T lymphocytes results in increased extracellular levels of β-chemokines: a strategy to inhibit R5 HIV-1. Proc Natl Acad Sci USA 2003; 100:4179–4184.

164. Rodriguez-Frade JM, Del Real G, Serrano A, Hernanz-Falcon P, Soriano SF, Vila-Coro AJ, et al. Blocking HIV-1 infection via CCR5 and CXCR4 receptors by acting in trans on the CCR2 chemokine receptor. EMBO J 2004; 23:66–76.

165. Shen W, Li B, Wetzel MA, Rogers TJ, Henderson EE, Su SB, et al. Down-regulation of the chemokine receptor CCR5 by activation of chemotactic formyl peptide receptor in human monocytes. Blood 2000; 96:2887–2894.

166. Gilliam BL, Heredia A, Devico A, Le N, Bamba D, Bryant JL, et al. Rapamycin reduces CCR5 mRNA levels in macaques: potential applications in HIV-1 prevention and treatment. AIDS 2007; 21:2108–2110.

167. Heredia A, Amoroso A, Davis C, Le N, Reardon E, Dominique JK, et al. Rapamycin causes down-regulation of CCR5 and accumulation of anti-HIV beta-chemokines: an approach to suppress R5 strains of HIV-1. Proc Natl Acad Sci USA 2003; 100:10411–10416.

168. Thivierge M, Le Gouill C, Tremblay MJ, Stankova J, Rola-Pleszcynski M. Prostaglandin E2 induces resistance to human immunodeficiency virus-1 infection in monocyte-derived macrophages: downregulation of CCR5 expression by cyclic adenosine monophosphate. Blood 1998; 92:40–45.

169. Nabatov AA, Pollakis G, Linnemann T, Paxton WA, de Baar MP. Statins disrupt CCR5 and RANTES expression levels in CD4+ T lymphocytes in vitro and preferentially decrease infection of R5 versus X4 HIV-1. PLoS ONE 2007; 5:e470.

170. Moncunill G, Negredo E, Bosch L, Vilarrasa J, Witvrouw M, Llano A, et al. Evaluation of the anti-HIV activity of statins. AIDS 2005; 19:1697–1700.

171. Juffermas NP, Verbon A, Olszyna DP, van Deventer SJ, Speelman P, van Der Poll T. Thalidomide suppresses up-regulation of human immunodeficiency virus coreceptors CXCR4 and CCR5 on CD4+ T cells in human. J Infect Dis 2000; 181:1813–1816.

172. Saccani A, Saccani S, Orlando S, Sironi M, Bernasconi S, Ghezzi P, et al. Redox regulation of chemokine receptor expression. Proc Natl Acad Sci USA 2000; 97:2761–2766.

173. Steinberger P, Andris-Widhopf J, Buhler B, Torbett BE, Barbas CFr. Functional deletion of the CCR5 receptor by intracellular immunization produces cells that are refractory to CCR5-dependent HIV-1 infection and cell fusion. Proc Natl Acad Sci USA 2000; 97:805–810.

174. Yang A-G, Bai X, Huang XF, Yao C, Chen S-Y. Phenotype knock-out of HIV type 1 chemokine receptor CCR-5 by intrakines as potential therapeutic approach for HIV-1 infection. Proc Natl Acad Sci USA 1997; 94:11567–11572.

175. Gonzalez MA, Serrano F, Llorente M, Abad JL, Garcia-Ortiz MJ. A hammerhead ribozyme targeted to the human chemokine receptor CCR5. Biochem Biophys Res Commun 1998; 251:592–596.

176. Qin XF, An DS, Chen IS, Baltimore D. Inhibiting HIV-1 infection in human T cells by lentiviral-mediated delivery of small interfering RNA against CCR5. Proc Natl Acad Sci USA 2002; 100:183–188.

Cited By:

This article has been cited 3 time(s).

Expert Review of Anti-Infective Therapy
The MOTIVATE trials: maraviroc therapy in antiretroviral treatment-experienced HIV-1-infected patients
van Lelyveld, SFL; Wensing, AMJ; Hoepelman, AIM
Expert Review of Anti-Infective Therapy, 10(): 1241-1247.
10.1586/ERI.12.114
CrossRef
Journal of Antimicrobial Chemotherapy
In vitro effects of the CCR5 inhibitor maraviroc on human T cell function
Arberas, H; Guardo, AC; Bargallo, ME; Maleno, MJ; Calvo, M; Blanco, JL; Garcia, F; Gatell, JM; Plana, M
Journal of Antimicrobial Chemotherapy, 68(3): 577-586.
10.1093/jac/dks432
CrossRef
Medecine Et Maladies Infectieuses
Impact of a new family on therapeutic strategies: immunologist point of view
Corbeau, P
Medecine Et Maladies Infectieuses, 39(): 13-15.

Back to Top | Article Outline
Keywords:

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

© 2009 Lippincott Williams & Wilkins, Inc.

Login

Search for Similar Articles
You may search for similar articles that contain these same keywords or you may modify the keyword list to augment your search.