A Moving Target: The Multiple Roles of CCR5 in Infectious Diseases
- Departments of Internal Medicine, of Infectious Diseases, of Pathology and Immunology, and of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri
- Reprints or correspondence: Robyn Klein, Dept. of Internal Medicine, of Infectious Diseases, of Pathology and Immunology, and of Anatomy and Neurobiology, Washington University School of Medicine, Campus Box 8051, 660 S. Euclid Ave., St. Louis, MO 63110 (rklein{at}id.wustl.edu).
Fifteen years after the identification of HIV-1 as the etiologic agent of AIDS [1], the chemokine receptor CCR5 was identified as one of the major coreceptors for macrophage-tropic viruses, the key pathogenic strains in vivo [2]. This discovery was shortly followed by the identification of an HIV-resistant population who carried a 32-bp deletion within the coding sequence of CCR5 (CCR5Δ32) that results in a complete loss of function of the receptor in homozygous individuals [3, 4]. The CCR5Δ32 allele remains the most important genetic factor associated with host resistance to HIV-1 infection and provided proof of principle that loss of CCR5 function could significantly impact HIV-1 infection. However, it took another 11 years for the development of a specific CCR5 antagonist that would prove efficacious in inhibiting viral progression in HIV-1—infected individuals [5, 6]. In the interim, research regarding the role played by CCR5 in a variety of inflammatory and infectious diseases has resulted in a complicated picture that suggests that CCR5 protects against diseases caused by certain pathogens but may also participate in postinfectious inflammatory responses that produce tissue injury and further pathology. In addition, CCR5 may play a role in the turnover of perivascular macrophages and microglia within the central nervous system (CNS), a process that may be responsible for delivery of HIV-1 to this site via infected macrophages. Thus, as we approach federal approval for use of the specific CCR5 antagonist maraviroc in HIV-1—infected individuals, our ability to predict an entirely favorable risk-benefit ratio during chronic use has become less clear.
As an example of this, in this issue of the Journal, 2 groups report that carriage of the CCR5Δ32 allele may be a risk factor for severe infections with flaviviruses. In one study, Kindberg et al. [7] performed CCR5Δ32 genotyping among Lithuanian patients with tickborne encephalitis (TBE), an often fatal infection caused by the TBE virus (TBEV). Infections with TBEV, a virus endemic to Europe and Asia, typically either induce a self-limited febrile illness with influenza-like symptoms or are asymptomatic. In certain individuals, for unknown reasons, TBEV induces severe meningoencephalitis. In these analyses, Kindberg et al. observed a significant increase in CCR5Δ32 allele prevalence in patients with TBE compared with that in patients with non-TBE aseptic meningoencephalitis and in healthy control subjects seronegative for TBEV. Although all individuals with CCR5Δ32 homozygosity were in the cohort with TBE, they were not members of the group with the most severe symptoms. Given that very little is known about the neuropathophysiology of TBE, the discovery of additional risk factors for severe neuroinvasive disease may eventually explain this apparent discrepancy.
In a parallel study, Lim et al. [8] demonstrated that functional CCR5 may be required to prevent symptomatic disease after infection with West Nile virus (WNV).WNVis an RNA flavivirus that is now endemic to North America and that can cause neuroinvasive disease, particularly in the elderly and immunocompromised, especially when cellular immunity is impaired [9, 10]. In immunocompetent individuals, WNV infection is similar to TBEV infection in that it most commonly induces either a self-limited febrile illness (West Nile fever [WNF]) or no symptoms at all [9]. The authors of this article had previously reported an association between CCR5 deficiency and increased WNV neuroinvasive disease in both CCR5−/− mice and 2 cohorts of patients with WNV infection from Colorado and Arizona [11, 12]. The study in the issue by Lim et al. is a replicative case-control study of 2 additional cohorts from Illinois and California that are smaller in size but that also indicate that homozygosity for the CCR5Δ32 allele is higher in patients with symptomatic WNV infection limited to WNF. This analysis did not demonstrate a connection between CCR5Δ32 and WNV neuroinvasive disease, as in the earlier human study; however, as indicated by the authors, the sample sizes were likely underpowered to show such an association for a gene found in populations of European descent with allelic frequencies ranging from 0 to 0.29 [13]. Nevertheless, a meta-analysis of all 4 cohorts supported a significant association between CCR5Δ32 homozygosity and symptomatic WNV infection.
The mechanism of CCR5-mediated protection from symptomatic WNV infection is unclear. As pointed out by Lim et al., because all of the WNV-infected subjects in all 4 cohorts had symptoms, no conclusions regarding the role played by CCR5 in the pathogenesis of WNV infection in humans could be made. Our current understanding of WNV pathogenesis comes from extensive studies using animal models, such as the mouse model used in the first study published by the authors of the current human analysis. In mice, viral replication occurs within dendritic cells soon after subcutaneous inoculation with WNV [14]. Dendritic cells migrate to regional lymph nodes, where innate immune responses, including the expression of interferons, hinder dissemination [15, 16]. Once viremia and dissemination occurs, however, adaptive immune responses in the form of antibody production and virus-specific cytotoxic T cells are required to clear virus from all infected compartments, including the CNS [17, 18]. Thus, susceptibility to WNV encephalitis in mice is increased when innate and adaptive immune responses are inhibited due to targeted deletion of molecules that participate in these responses [12, 19–21]. That CCR5 is specifically required for CNS leukocyte trafficking for the purpose of viral clearance is evidenced by the increased viral burdens and decreased NK and mononuclear cells observed in the brains of CCR5-deficient mice. Data from several recent studies examining innate immune responses in CCR5−/− mice infected with a variety of pathogens are consistent with these results. Thus, loss of CCR5 is associated with decreased granulocyte and NKcell recruitment during infection with Trypanosoma cruzi [22, 23], Toxoplasma gondii [24], and herpes simplex virus types 1 and 2 [25, 26]. Interestingly, WNV infection is the first example of an infection in which CCR5 directs a T cell response aimed at pathogen elimination rather than counterregulation.
Most data on the role played by CCR5 and adaptive immune responses to infectious diseases suggest a role for the receptor in counterregulatory T cell responses that limit the control of intracellular pathogens but that also protect against postinfectious inflammatory responses. In a mouse model of viral hepatitis, loss of CCR5 led to accelerated T cell responses and induction of CD8+ T cell—mediated immunopathology [27]. Similarly, CCR5−/− mice have inefficient migration of CD4+ regulatory T cells to the site of Leishmania major infestation, resulting in reduced parasite numbers and resistance to infection [28]. In human studies, Barr et al. [29] reported a significant positive correlation between carriage of the allele and lack of pathological changes in the fallopian tubes of women exposed to Chlamydia trachomatis genital infections. This effect was reproduced in murine models comparing CCR5-deficient and wild-type animals—although clearance of genital chlamydial infection was delayed in the short term, the fertility of infected mice was significantly altered only in wild-type mice. In addition, several studies evaluating patients chronically infected with hepatitis C virus have suggested that the CCR5Δ32 allele does not affect disease susceptibility or viral clearance but may be associated with a decrease in liver inflammation, as assessed by histopathological analysis of tissue biopsy specimens [30]. In contrast, recovery from hepatitis B, which requires a vigorous T cell response, is enhanced in individuals with CCR5 polymorphisms [31]. Finally, several studies have examined the role played by CCR5 in Chagas disease cardiomyopathy, a sequela of infection with the parasite Trypanosoma cruzi, through the analysis of CCR5 gene polymorphisms [32]. Although there did not appear to be an association between the frequency of the CCR5Δ32 allele and infection rates, once again there appeared to be a positive correlation between altered receptor function and lack of progression to inflammatory cardiac disease.
The biology of CCR5 in the context of flavivirus-induced encephalitides may suggest more about the role played by this molecule in the trafficking of mononuclear cells into the CNS and thus, ultimately, in HIV-1 neurotropism. Under normal circumstances, perivascular macrophages are continuously replaced by bone marrow—derived monocytes [33]. The molecular mechanisms that orchestrate the turnover of perivascular macrophages are unknown; however, these cells express both classes of HIV-1 coreceptors (because they are derived from bonemarrow stem cells, which express CXCR4) and additionally acquire expression of CCR5 during differentiation into monocytes [34]. Thus, the effects of HIV-1 coreceptor antagonists on the spread of HIV-1 into the human CNS are important considerations in the evaluation of these antiviral approaches, because they could enhance or inhibit the CNS as a viral sanctuary, thereby affecting the prevalence of neuroAIDS. Macrophage tropism has traditionally been defined as the ability of an HIV-1 strain to infect macrophages and microglia preferentially over lymphocytes [35]. Contrary to prior analyses, recent data have suggested that these viruses do not necessarily use CCR5 for viral entry [36]. Thus, use of CCR5 antagonists may facilitate the entry of viruses that use CXCR4 (R4 viruses), and macrophages infected with R4 viruses may deliver these potentially neurotoxic HIV-1 strains to the CNS [37]. If CCR5 antagonists derail leukocyte trafficking into the CNS, as has been suggested by studies examining WNV infection of CCR5-deficient mice, then they could potentially inhibit the trafficking of these infected macrophages into the CNS. Alternatively, if CCR5-expressing monocytes that bring HIV-1 into the brain are instead localized to the perivascular space via CCR5 ligands expressed by perivascular macrophages [38], then CCR5 inactivation might enhance intraparenchymal migration of these infected cells, thereby boosting CNS viral loads.
In summary, there are ample data to suggest that CCR5 is involved in both positive and negative regulation of immune functions that relate to the regulation of leukocyte trafficking during infectious and postinfectious diseases. Thus, although there is reason to be optimistic about the development of CCR5 antagonists for the treatment of HIV-1 infection, it is also reasonable to hypothesize that antagonism of CCR5 will be advantageous in certain circumstances but disadvantageous in others. Although immunization against WNV or TBEV before the initiation of treatment with CCR5 antagonists for HIV-1 infection might be one strategy to use to prevent symptomatic flavivirus infections, there are numerous other possible infectious sequelae that may be exacerbated by CCR5 inactivation for which we have no preventive measures. Therefore, although it is exciting to imagine that we are on the brink of an era during which targeted therapies based on extensive knowledge of immune function will provide safer treatment options for infectious diseases such as AIDS, it is more likely that the ultimate application, utility, and safety of these therapies will have to be determined empirically, as with all other drugs that have come before them.
Footnotes
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Potential conflicts of interest: none reported.
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Financial support: National Institute of Neurological Disorders and Stroke, National Institutes of Health (grants K02NS045607 and R01NS052632); National Multiple Sclerosis Society (grant RG3982A); Dana Foundation; Midwest Regional Center for Excellence in Biodefense and Emerging Infectious Diseases; McDonnell Center for Cellular and Molecular Neurobiology.
- Received July 30, 2007.
- Accepted July 31, 2007.
- © 2008 by the Infectious Diseases Society of America
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