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Current Opinion in HIV & AIDS:
doi: 10.1097/COH.0b013e3283223d76
Entry inhibitors: Edited by Jose A. Este

Safety concerns about CCR5 as an antiviral target

Telenti, Amalio

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Institute of Microbiology, University Hospital Center, University of Lausanne, Lausanne, Switzerland

Correspondence to Amalio Telenti, Institute of Microbiology, CHUV, 1011 Lausanne, Switzerland Tel: +41 21 314 0550; e-mail: Amalio.Telenti@chuv.ch

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Abstract

Purpose of review: Clinical trials of CCR5 antagonists attest to their efficacy and tolerance in HIV treatment. However, there has been debate on their long-term safety because of the role of CCR5 in innate immunity. This review highlights gaps in our understanding of epidemiology of infections that are modulated by CCR5, in particular, in HIV-infected individuals.

Recent findings: In the mouse model, CCR5 has a role in the response against pathogens as diverse as Toxoplama gondii, West Nile virus, Mycobacterium tuberculosis, herpes simplex virus, Trypanosoma cruzi, Cryptococcus neoformans, Chlamydia trachomatis, Listeria, and plasmodia. In human cohorts, individuals carrying the defective CCR5Δ32 allele present an increased susceptibility to flavivirus (West Nile virus and tickborne encephalitis virus). The selective pressures that led to the spread of loss-of-function CCR5 mutations in humans (CCR5Δ32), and in mangabeys (CCR5Δ24) are not understood.

Summary: The recent availability of CCR5 antagonists has raised concern that genetic, biological, or chemical CCR5 knockout, although beneficial against some pathogens (i.e. HIV), could be deleterious for other processes implicated in pathogen response. The consequences of long-term pharmaceutical intervention on CCR5 should be carefully assessed through rigorous postmarketing surveillance.

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Introduction

The chemokine receptor 5 (CCR5) is expressed on Th1 and Th0 cells, macrophages, and immature dendritic cells. The receptor binds CCL3, CCL4, and CCL5 chemokines, thereby helping the initiation of immune responses and the distribution of effector immune cells to sites of inflammation (reviewed in [1,2]). Accordingly, a number of recent studies highlight a complex role of CCR5 in innate immunity against a number of pathogens as diverse as Toxoplama gondii, West Nile virus (WNV), tickborne encephalitis virus, Mycobacterium tuberculosis, herpes simplex virus, Trypanosoma cruzi, Cryptococcus neoformans, Chlamydia trachomatis, hepatitis B virus, Listeria, and plasmodia [3–10,11•,12,13]. Laboratory and animal experimental data indicate that there may be a delicate equilibrium between pathogen containment and undesirable immune response mediated by CCR5.

The recent availability of CCR5 antagonists [14] has raised concern that genetic, biological, or chemical CCR5 knockout, although beneficial against some pathogens (i.e. HIV), could be deleterious for other processes implicated in pathogen response. The immune system may have substantial redundancy and provide a good general protection to most pathogens, while hiding selective defects if exposed to a sufficient challenge of a particular pathogen. Thus, any pharmaceutical intervention on innate immunity may uncover selective immunodeficiency. This fact is illustrated by the experience with anti-TNFα therapy and the identification, during postmarketing surveillance, of an increased risk for reactivation of tuberculosis [15].

Beyond considerations regarding conventional toxicity and pharmacovigilance for the new class of antiretroviral agents, this review will focus the discussion on the specific issues related to the chronic blockade of the CCR5 receptor. For this, the discussion includes a view on the origin of the CCR5 deletion CCR5Δ32 in humans, on the consequences of CCR5 knockout in animal models, and on the evidence of modulation of susceptibility to certain infectious and inflammatory diseases by the CCR5Δ32 allele. The review highlights gaps in our understanding of epidemiology of infections that are modulated by CCR5, in particular, in HIV-infected individuals.

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Origin of CCR5 and the CCR5Δ32 deletion

The human CC chemokine receptor family includes 10 genes (CCR110), and homologous genes have been described in placental mammals [16]. Receptors CCR1 through CCR5 are very similar in structure, suggesting an origin through gene duplication from a common ancestor [17]. The locus CCR2–CCR5 is closely related in terms of sequence similarity and in physical distance on chromosome 3. This facilitates evolution of the locus through mechanisms of gene conversion that would generate similar transmembrane structures and facilitate CCR2 and CCR5 heterodimerization [16,18]. The concerted evolution of the CCR2 and CCR5 locus is at the origin of a CCR5/2 recombinant gene identified in horses, which could be relevant in the understanding of the susceptibility of this species to West Nile viral infection [19].

Understanding the evolutionary origins of the CCR5 deletion (CCR5Δ32) in humans may help define the selective pressures that led to its fixation in humans. The geographic spread of CCR5Δ32 has been investigated in detail [20]. This allele is found only in European, West Asian, and North African populations, and exhibits a north–south pattern of decreasing frequency. Although presented as a paradigm of natural selection of an advantageous allele in humans, there is still significant controversy regarding the selective pressures that led to the spread of the allele, or even on whether there is evidence of positive selection [21]. Although the variant was proposed to be a recent response to plague or smallpox, research on Bronze Age samples, and on 14th century plague victims indicate that the presence of the allele, and the regional differences in frequency in the European population ante-date medieval times [22]. In particular, the high frequency of CCR5Δ32 in the Bronze Age (>3000 years ago) predates the time during which plague or smallpox were prevalent. Overall, there are no clues on particular pathogens or other selective pressures (if any) that acted on the CCR5 locus, nor evidence on disadvantage association with the CCR5Δ32 deletion.

The coding region of CCR5 is under purifying selection in primates, although more genetic diversity may be observed in New World monkeys [23]. However, like in humans, CCR5 deletions have also been observed in the red-capped mangabeys and in sooty mangabeys [24]. The 24-bp in-frame deletion (CCR5Δ24) in the fourth transmembrane region is present at high allelic frequency in this species. CCR5Δ24 does not support R5-tropic lentivirus infection and fails signal transduction assays mediated by B-chemokines [24]. Interestingly, red-capped mangabeys are infected by a simian immunodeficiency virus (SIV) strain that is not R5-tropic but uses CCR2b as its major coreceptor, suggesting that the shift of tropism may be an adaptation of SIVrcm to the CCR5 genetic defect in the host [24]. The deletions in monkeys and in humans, although different, may represent a similar response to selective pressures (convergent evolution).

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Animal and in-vitro studies of CCR5 deficiency

There have been a number of studies that examined the role of CCR5 in viral, bacterial, fungal, and parasitic diseases. The task was facilitated by the availability of CCR5 knockout mice (ccr5−/−) [13]. These animals do not present any developmental defect. CCR5-deficient mice exhibit a more robust T-cell response to a number of antigens [13,25,26]. In the mouse model of WNV infection, several chemokines and chemokine receptors are consistently upregulated; including CCR5 and its ligands CCL3, CCL4, and CCL5. When ccr5−/− mice were infected intradermally with WNV, infection was uniformly fatal in contrast to wild-type mice in which the majority survived [4]. Spleens from infected wild-type and ccr5−/− mice were cleared of virus at equal rates, and the distributions of leukocyte subsets, including interferon-γ (INF-γ)+ T-cells, were similar. By contrast, CCR5-deficient mice could not control virus replication in the CNS, and this was associated with the reduced accumulation of infiltrating CD4+ and CD8+ T cells, natural killer cells, and macrophages [4]. However, resolution of CNS infection is often a balance between immune-mediated pathogen clearance and the deleterious effects of inflammation. Recently, McCandless et al. [27] reported that antagonism of another chemokine receptor, CXCR4, in an AMD3100-treated mice model resulted in increased intraparenchymal T-cell migration and improved outcome of WNV encephalitis.

The mouse model has been also used to assess the role of CCR5 in host defense during a generalized herpes simplex virus type 2 (HSV-2) infection [6]. Significantly higher virus titres were seen in the livers and brains of 4-week-old ccr5−/− mice compared with wild-type animals. However, at the age of 8 weeks, ccr5−/− mice were indistinguishable from wild-type mice and cleared the infection from liver and spleen. Thus, this study suggested that CCR5 plays an age-dependent role in host defense against HSV-2.

The role of CCR5 in viral infections extends beyond its specific capacity as viral receptor or in immune response. Rahbar et al. [28] described the influence of modulating CCR5 expression and activation on the permissive phenotype in the context of infecting vaccinia poxvirus. Mature virus enters both permissive and nonpermissive T-cell lines. Expression of CCR5 in nonpermissive mouse fibroblast or human primary T cells renders the cells permissive for vaccinia replication. T cells expressing CCR5 in which tyrosine 339 in the intracellular region is replaced by phenylalanine no longer support virus replication or virus-inducible activation of specific host cell signaling effectors [28].

CCR5 may also participate in the response to bacteria and bacterial products such as lipopolysaccharide (LPS) and heat shock proteins. Peritoneal macrophages from CCR5-deficient mice after LPS challenge were much smaller in size and less foamy compared with those from wild-type mice, indicating they are less active than wild-type macrophages. This was associated with a minor reduced efficiency in clearance of Listeria infection and a protective effect against LPS-induced endotoxemia, suggesting a partially defective macrophage function [13]. The microbial 70-kDa heat shock protein (HSP70) binds to CCR5, thus influencing the pathophysiology of tuberculosis [5]. Whittall et al. [29] examined immature dendritic cells with high CCR5 expression, mature dendritic cells with low CCR5 expression, and dendritic cells from CCR5Δ32 homozygotes. A dose-dependent increase of IL-12 or TNF-α production was demonstrated by stimulation with HSP70 of immature dendritic cells (CCR5 16.1%), compared with no change in the production of either IL-12 or TNF-α of mature dendritic cells (CCR5 1.8%). Immature dendritic cells prepared from a subject homozygous for CCR5Δ32 failed to be stimulated at low concentrations of HSP70.

CCR5 influences natural killer cell function and host (CCR5−/− mice) survival in Toxoplama gondii [3]. CCR5 has been implicated in host defense against Trypanosoma cruzi [7,30], malaria [8], Cryptococcus neoformans [9], and Chlamydia trachomatis [10].

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Cohort studies

Cohort studies (unrelated to HIV infection) provided the first clinical evidence of a possible nonneutral effect of CCR5 deficiency via the allele CCR5Δ32 [31]. The first data associated CCR5 deficiency with symptomatic WNV infection in the United States [32]. The original study was followed by the reporting of the association of CCR5 deficiency with susceptibility to other flaviviruses [11•].

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West Nile virus

The study of the group of Murphy on cohorts of individuals with WNV infection from Arizona (n = 247) and Colorado (n = 145) identified a 4.5 increase in odds ratio (OR) in susceptibility to symptomatic WNV disease [32]. The same group extended this work to include data from cohorts from California and Illinois [33••]. Their meta-analytical estimates confirmed the initial findings.

Does the immunosuppressive effect of HIV infection (independently of the use of CCR5 antagonists) place individuals at risk for more severe WNV infection? To date, there have only been five case reports of WNV infection occurring among HIV-1-infected individuals. HIV infection was present in two of 23 individuals who died with WNV encephalomyelitis [34]. A separate study describes an individual presenting with acute onset of quadriplegia after WNV infection in the context of profound HIV-1 immunosuppression (CD4 T cell count of 93 cells/μl, no antiretroviral treatment) who died [35]. Two additional studies in the literature described recovery. The first study presents a case of acute flaccid monoparesis of the right upper extremity in the presence of moderate immunosuppression (CD4 T-cell count of 324 cells/μl, no antiretroviral treatment) [36]. The second study describes a case of WNV encephalitis in a woman with CD4 T cell count of 351 cells/μl and controlled HIV-1 viremia in the presence of antiretroviral therapy [37]. There are no currently available data on WNV–HIV co-infection among individuals receiving CCR5 antagonists as part of their antiretroviral treatment. A possible risk associated with their use will need to be evaluated against a setting of suboptimal understanding of the epidemiology and clinical importance of WNV–HIV co-infection.

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Tickborne encephalitis

Tickborne encephalitis (TBE) virus, endemic in areas of Europe and Asia, is transmitted to humans by Ixodes ricinus and I. persulcatus ticks. This pathogen also belongs to the genus flavivirus. WNV and TBEV share neurotropism as a common property. Kindberg et al. [11•] investigated the association of CCR5Δ32 and TBE in Lithuanian patients with TBE (n = 129) or with aseptic meningoencephalitis (n = 76), as well as among a control population (n = 134). They found individuals homozygous for CCR5Δ32 (n = 3) only among patients with TBE, and a higher allele prevalence among TBE patients compared with the other groups studied. As described for WNV infection, the CCR5Δ32 allele frequency increased with the severity of disease. Other members of the genus flavivirus, yellow fever and dengue viruses, are important pathogens worldwide, but no study exists on whether CCR5 deficiency influences disease.

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Hepatitis C

A possible association of CCR5 on response to hepatitis C virus (HCV) infection is of relevance given that the population susceptible to receive a CCR5 antagonist has a high proportion of co-infected individuals. Wheeler et al. [38•] evaluated 14 studies published between 2002 and 2006 on the association of CCR5Δ32 and susceptibility to HCV infection. These studies compared the CCR5Δ32 allele frequency in 1921 cases versus the frequency in 4267 controls. The meta-analysis could find no association between genotype and susceptibility to HCV. Wheeler et al. [38•] also evaluated nine publications on 1562 patients reporting on response to IFN-α with or without ribavirin. Point estimates of seven studies assessing response to the current standard of IFB-α/ribavirin (defined as HCV RNA negative 6 months after initial therapy) suggested a more limited response among individuals carrying the CCR5Δ32 allele [meta-analysis OR 0.72; 95% confidence interval (CI): 0.50–1.04]. Studies of disease severity, for example, on the association between CCR5Δ32 and liver fibrosis, were of insufficient consistency for a meta-analytical summary. One study investigated the spontaneous elimination of HCV among a cohort of women infected from a common source, reporting an adverse effect of CCR5Δ32 carriage [39].

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Hepatitis B

Given the importance of the T-cell response in hepatitis B recovery and the proposed role of CCR5 in modulating response to several antigens, Thio et al. [12] studied 526 individuals from three cohorts in which one person with hepatitis B virus (HBV) persistence was matched to two persons who recovered from an HBV infection. In this analysis, CCR5Δ32 reduced the risk of persistence by nearly half (OR 0.53). This association was observed in individuals with and without concomitant HIV-1 infection. The data also suggested a gene dosage effect, as one copy of CCR5Δ32 was intermediate in protective effect between zero and two copies. Interestingly, CCR5 expression can modulate the severity of immune-mediated liver injury. Moreno et al. [40] reported, in a concanavalin A model of liver injury, that CCR5-deficient (ccr5−/−) mice had increased mortality compared with wild-type mice. In this model, CCR5 deficiency exacerbated T-cell-mediated hepatitis, leading to a more pronounced liver mononuclear infiltration.

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Noninfectious diseases

The meta-analysis of Wheeler et al. [38•] did not show an increased risk of development of multiple sclerosis in the presence of CCR5Δ32. In contrast, CCR5Δ32 might be protective against the development of rheumatoid arthritis [38•,41]. An improvement in survival after renal transplantation has been reported in patients homozygous for CCR5Δ32 [42].

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Conclusion

The immune system has substantial redundancy, but defects can manifest if the host is exposed to a sufficient challenge of a specific pathogen, or due to pharmacological disruption. In April 2007, the Antiviral Advisory Committee of the FDA recommended approval of maraviroc. Pfizer initiated an expanded access program to assess the consequences of long-term pharmaceutical intervention on the pathways of CCR5 and other chemokine receptors on innate immunity, and on issues such as hepatic toxic effects and the risk of malignant disease. The second CCR5 antagonist under clinical evaluation, vicriviroc (Schering-Plough), was initially associated with the development of malignant tumours [43]. However, no clinically relevant differences in safety profile between the vicriviroc and control groups were observed at 48 weeks.

The recent publication of two large-scale trials of the efficacy of the CCR5 antagonist maraviroc proved the administration of the drug is well tolerated [44,45]. However, as once more indicated in the accompanying editorial, ‘Whether pharmacologic interference with the function of the CCR5 receptor is analogous to a congenital absence of the receptor is not clear. Longer term studies of the effects of CCR5 inhibition, particularly those involving immune functions, need to be carried out’ [46]. Postmarketing surveillance for this drug class is essential. Until more information is available, consideration should be given to general recommendations to limit exposure to mosquitoes or even to immunization in high-risk regions (e.g. for tickborne viral encephalitis) among persons receiving treatment with CCR5 antagonists.

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Acknowledgements

Work in my laboratory is supported by the Swiss National Science Foundation.

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References and recommended reading

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Papers of particular interest, published within the annual period of review, have been highlighted as:

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• of special interest

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•• of outstanding interest

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Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 162).

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Keywords:

CCR5 antagonists; CCR5Δ32; maraviroc; vicriviroc

© 2009 Lippincott Williams & Wilkins, Inc.

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