Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

CCR5 blockade for neuroinflammatory diseases — beyond control of HIV

Nature Reviews Neurology volume 12, pages 95–105 (2016)Cite this article

Subjects

Key Points

  • Chemokine receptors (CCRs) influence several facets of the immune response and have been implicated in a wide range of inflammatory diseases, including some that affect the CNS

  • Correlative evidence implicates the CCR5–CCL3/CCL5 axis in multiple sclerosis, Rasmussen encephalitis, progressive multifocal leukoencephalopathy-associated immune reconstitution inflammatory syndrome and infectious diseases, such as cerebral malaria and HIV-associated neurocognitive disorders

  • Maraviroc is an antagonist of CCR5 that was originally developed for the treatment of HIV and is already on the market and well tolerated by patients

  • Maraviroc might provide neuroprotection in settings in which CCR5 contributes to deleterious neuroinflammation, particularly in diseases in which CD8+ T cells play a pivotal role

  • Preclinical and clinical studies that assess the benefits of maraviroc in these settings are warranted

Abstract

Chemokine receptors have been implicated in a wide range of CNS inflammatory diseases and have important roles in the recruitment and positioning of immune cells within tissues. Among them, the chemokine (C–C motif) receptor 5 (CCR5) can be targeted by maraviroc, a readily available and well-tolerated drug that was developed for the treatment of HIV. Correlative evidence implicates the CCR5–chemokine axis in multiple sclerosis, Rasmussen encephalitis, progressive multifocal leukoencephalopathy-associated immune reconstitution inflammatory syndrome, and infectious diseases, such as cerebral malaria and HIV-associated neurocognitive disorders. On the basis of this evidence, we postulate in this Review that CCR5 antagonists, such as maraviroc, offer neuroprotective benefits in settings in which CCR5 promotes deleterious neuroinflammation, particularly in diseases in which CD8+ T cells seem to play a pivotal role.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Role of CCR5 in neuroinflammatory diseases, and potential benefits of CCR5 blockade.
Figure 2: CCR5 in inflammatory brain diseases.
Figure 3: Prevention of PML-IRIS in natalizumab-associated inflammatory PML.

Similar content being viewed by others

References

  1. Griffith, J. W., Sokol, C. L. & Luster, A. D. Chemokines and chemokine receptors: positioning cells for host defense and immunity. Annu. Rev. Immunol. 32, 659–702 (2014).

    Article  CAS  PubMed  Google Scholar 

  2. Cardona, S. M., Garcia, J. A. & Cardona, A. E. The fine balance of chemokines during disease: trafficking, inflammation, and homeostasis. Methods Mol. Biol. 1013, 1–16 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Henrich, T. J. & Kuritzkes, D. R. HIV-1 entry inhibitors: recent development and clinical use. Curr. Opin. Virol. 3, 51–57 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Luther, S. A. & Cyster, J. G. Chemokines as regulators of T cell differentiation. Nat. Immunol. 2, 102–107 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Luster, A. D. The role of chemokines in linking innate and adaptive immunity. Curr. Opin. Immunol. 14, 129–135 (2002).

    Article  CAS  PubMed  Google Scholar 

  6. Nieto, M. et al. Roles of chemokines and receptor polarization in NK-target cell interactions. J. Immunol. 161, 3330–3339 (1998).

    CAS  PubMed  Google Scholar 

  7. Park, M. H. et al. Chemokines released from astrocytes promote chemokine receptor 5-mediated neuronal cell differentiation. Exp. Cell Res. 315, 2715–2726 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. Shukaliak, J. A. & Dorovini-Zis, K. Expression of the β-chemokines RANTES and MIP-1β by human brain microvessel endothelial cells in primary culture. J. Neuropathol. Exp. Neurol. 59, 339–352 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Subileau, E. A. et al. Expression of chemokines and their receptors by human brain endothelium: implications for multiple sclerosis. J. Neuropathol. Exp. Neurol. 68, 227–240 (2009).

    Article  CAS  PubMed  Google Scholar 

  10. Ferguson, A. R. & Engelhard, V. H. CD8 T cells activated in distinct lymphoid organs differentially express adhesion proteins and coexpress multiple chemokine receptors. J. Immunol. 184, 4079–4086 (2010).

    Article  CAS  PubMed  Google Scholar 

  11. Castellino, F. et al. Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell-dendritic cell interaction. Nature 440, 890–895 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Hickman, H. D. et al. Chemokines control naive CD8+ T cell selection of optimal lymph node antigen presenting cells. J. Exp. Med. 208, 2511–2524 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Semmling, V. et al. Alternative cross-priming through CCL17–CCR4-mediated attraction of CTLs toward NKT cell-licensed DCs. Nat. Immunol. 11, 313–320 (2010).

    Article  CAS  PubMed  Google Scholar 

  14. Hugues, S. et al. Dynamic imaging of chemokine-dependent CD8+ T cell help for CD8+ T cell responses. Nat. Immunol. 8, 921–930 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Molon, B. et al. T cell costimulation by chemokine receptors. Nat. Immunol. 6, 465–471 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Camargo, J. F. et al. CCR5 expression levels influence NFAT translocation, IL-2 production, and subsequent signaling events during T lymphocyte activation. J. Immunol. 182, 171–182 (2009).

    Article  CAS  PubMed  Google Scholar 

  17. Contento, R. L. et al. CXCR4–CCR5: a couple modulating T cell functions. Proc. Natl Acad. Sci. USA 105, 10101–10106 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sheridan, B. S. & Lefrançois, L. Regional and mucosal memory T cells. Nat. Immunol. 12, 485–491 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sallusto, F., Lenig, D., Mackay, C. R. & Lanzavecchia, A. Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. J. Exp. Med. 187, 875–883 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Fukada, K., Sobao, Y., Tomiyama, H., Oka, S. & Takiguchi, M. Functional expression of the chemokine receptor CCR5 on virus epitope-specific memory and effector CD8+ T cells. J. Immunol. 168, 2225–2232 (2002).

    Article  CAS  PubMed  Google Scholar 

  21. Kohlmeier, J. E. et al. The chemokine receptor CCR5 plays a key role in the early memory CD8+ T cell response to respiratory virus infections. Immunity 29, 101–113 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Weninger, W., Biro, M. & Jain, R. Leukocyte migration in the interstitial space of non-lymphoid organs. Nat. Rev. Immunol. 14, 232–246 (2014).

    Article  CAS  PubMed  Google Scholar 

  23. Ubogu, E. E., Callahan, M. K., Tucky, B. H. & Ransohoff, R. M. CCR5 expression on monocytes and T cells: modulation by transmigration across the blood–brain barrier in vitro. Cell. Immunol. 243, 19–29 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Quandt, J. & Dorovini-Zis, K. The β chemokines CCL4 and CCL5 enhance adhesion of specific CD4+ T cell subsets to human brain endothelial cells. J. Neuropathol. Exp. Neurol. 63, 350–362 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Kohlmeier, J. E. et al. Inflammatory chemokine receptors regulate CD8+ T cell contraction and memory generation following infection. J. Exp. Med. 208, 1621–1634 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Das, S. et al. Immune subversion by Mycobacterium tuberculosis through CCR5 mediated signaling: involvement of IL-10. PLoS ONE 9, e92477 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Kitade, H. et al. CCR5 plays a critical role in obesity-induced adipose tissue inflammation and insulin resistance by regulating both macrophage recruitment and M1/M2 status. Diabetes 61, 1680–1690 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Rossi, R. et al. In vitro effect of anti-human immunodeficiency virus CCR5 antagonist maraviroc on chemotactic activity of monocytes, macrophages and dendritic cells. Clin. Exp. Immunol. 166, 184–190 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chang, L. Y. et al. The indispensable role of CCR5 for in vivo suppressor function of tumor-derived CD103+ effector/memory regulatory T cells. J. Immunol. 189, 567–574 (2012).

    Article  CAS  PubMed  Google Scholar 

  30. Dolan, M. J. et al. CCL3L1 and CCR5 influence cell-mediated immunity and affect HIV-AIDS pathogenesis via viral entry-independent mechanisms. Nat. Immunol. 8, 1324–1336 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Zhou, Y. 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. 160, 4018–4025 (1998).

    CAS  PubMed  Google Scholar 

  32. Dragic, T. et al. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature 381, 667–673 (1996).

    Article  CAS  PubMed  Google Scholar 

  33. Nguyêñ, G. T. et al. Phenotypic expressions of CCR5-Δ32/Δ32 homozygosity. J. Acquir. Immune Defic. Syndr. 22, 75–82 (1999).

    Article  PubMed  Google Scholar 

  34. Rottman, J. B. et al. Cellular localization of the chemokine receptor CCR5. Correlation to cellular targets of HIV-1 infection. Am. J. Pathol. 151, 1341–1351 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Westmoreland, S. V. et al. Developmental expression patterns of CCR5 and CXCR4 in the rhesus macaque brain. J. Neuroimmunol. 122, 146–158 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Choi, D. Y., Lee, M. K. & Hong, J. T. Lack of CCR5 modifies glial phenotypes and population of the nigral dopaminergic neurons, but not MPTP-induced dopaminergic neurodegeneration. Neurobiol. Dis. 49, 159–168 (2013).

    Article  CAS  PubMed  Google Scholar 

  37. Klein, R. S. et al. Chemokine receptor expression and signaling in macaque and human fetal neurons and astrocytes: implications for the neuropathogenesis of AIDS. J. Immunol. 163, 1636–1646 (1999).

    CAS  PubMed  Google Scholar 

  38. Meucci, O. et al. Chemokines regulate hippocampal neuronal signaling and gp120 neurotoxicity. Proc. Natl Acad. Sci. USA 95, 14500–14505 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Martinson, J. J., Chapman, N. H., Rees, D. C., Liu, Y. T. & Clegg, J. B. Global distribution of the CCR5 gene 32-basepair deletion. Nat. Genet. 16, 100–103 (1997).

    Article  CAS  PubMed  Google Scholar 

  40. Novembre, J., Galvani, A. P. & Slatkin, M. The geographic spread of the CCR5 Δ32 HIV-resistance allele. PLoS Biol. 3, e339 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Dean, M. et al. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Science 273, 1856–1862 (1996).

    Article  CAS  PubMed  Google Scholar 

  42. Ioannidis, J. P. et al. Effects of CCR5-Δ32, CCR2-64I, and SDF-1 3′A alleles on HIV-1 disease progression: an international meta-analysis of individual-patient data. Ann. Intern. Med. 135, 782–795 (2001).

    Article  CAS  PubMed  Google Scholar 

  43. Walker, W. E. et al. Increased levels of macrophage inflammatory proteins result in resistance to R5-tropic HIV-1 in a subset of elite controllers. J. Virol. 89, 5502–5514 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Baba, M. et al. TAK-652 inhibits CCR5-mediated human immunodeficiency virus type 1 infection in vitro and has favorable pharmacokinetics in humans. Antimicrob. Agents Chemother. 49, 4584–4591 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Gulick, R. M. et al. Five-year safety evaluation of maraviroc in HIV-1-infected treatment-experienced patients. J. Acquir. Immune Defic. Syndr. 65, 78–81 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lazzarin, A. et al. The maraviroc expanded access program — safety and efficacy data from an open-label study. HIV Clin. Trials 16, 10–21 (2015).

    Article  PubMed  Google Scholar 

  47. Llibre, J. M. et al. Safety, efficacy and indications of prescription of maraviroc in clinical practice: factors associated with clinical outcomes. Antiviral Res. 120, 79–84 (2015).

    Article  CAS  PubMed  Google Scholar 

  48. Fätkenheuer, G. et al. Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1. Nat. Med. 11, 1170–1172 (2005).

    Article  PubMed  CAS  Google Scholar 

  49. Gulick, R. M. et al. Maraviroc for previously treated patients with R5 HIV-1 infection. N. Engl. J. Med. 359, 1429–1441 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Tan, Q. et al. Structure of the CCR5 chemokine receptor-HIV entry inhibitor maraviroc complex. Science 341, 1387–1390 (2013).

    Article  CAS  PubMed  Google Scholar 

  51. Dorr, P. et al. Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob. Agents Chemother. 49, 4721–4732 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Wilkin, T. J., Ribaudo, H. R., Tenorio, A. R. & Gulick, R. M. The relationship of CCR5 antagonists to CD4+ T-cell gain: a meta-regression of recent clinical trials in treatment-experienced HIV-infected patients. HIV Clin. Trials 11, 351–358 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Cuzin, L. et al. Maraviroc intensification of stable antiviral therapy in HIV-1-infected patients with poor immune restoration: MARIMUNO-ANRS 145 study. J. Acquir. Immune Defic. Syndr. 61, 557–564 (2012).

    Article  CAS  PubMed  Google Scholar 

  54. Rossi, R. et al. Downregulation of leukocyte migration after treatment with CCR5 antagonist maraviroc. J. Acquir. Immune Defic. Syndr. 54, e13–e14 (2010).

    Article  PubMed  Google Scholar 

  55. Arberas, H. et al. In vitro effects of the CCR5 inhibitor maraviroc on human T cell function. J. Antimicrob. Chemother. 68, 577–586 (2013).

    Article  CAS  PubMed  Google Scholar 

  56. Funderburg, N. et al. Effects of maraviroc and efavirenz on markers of immune activation and inflammation and associations with CD4+ cell rises in HIV-infected patients. PLoS ONE 5, e13188 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Romero-Sánchez, M. C. et al. Effect of maraviroc on HIV disease progression-related biomarkers. Antimicrob. Agents Chemother. 56, 5858–5864 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Gutiérrez, C. et al. Intensification of antiretroviral therapy with a CCR5 antagonist in patients with chronic HIV-1 infection: effect on T cells latently infected. PLoS ONE 6, e27864 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Pozo-Balado, M. M. et al. Maraviroc reduces the regulatory T-cell frequency in antiretroviral-naive HIV-infected subjects. J. Infect. Dis. 210, 890–898 (2014).

    Article  CAS  PubMed  Google Scholar 

  60. Clifford, D. B. & Ances, B. M. HIV-associated neurocognitive disorder. Lancet Infect. Dis. 13, 976–986 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Canestri, A. et al. Discordance between cerebral spinal fluid and plasma HIV replication in patients with neurological symptoms who are receiving suppressive antiretroviral therapy. Clin. Infect. Dis. 50, 773–778 (2010).

    Article  PubMed  Google Scholar 

  62. Letendre, S. et al. Validation of the CNS Penetration-Effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch. Neurol. 65, 65–70 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Letendre, S. Central nervous system complications in HIV disease: HIV-associated neurocognitive disorder. Top. Antivir. Med. 19, 137–142 (2011).

    PubMed  Google Scholar 

  64. Cysique, L. A., Waters, E. K. & Brew, B. J. Central nervous system antiretroviral efficacy in HIV infection: a qualitative and quantitative review and implications for future research. BMC Neurol. 11, 148 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Vassallo, M. et al. Can high central nervous system penetrating antiretroviral regimens protect against the onset of HIV-associated neurocognitive disorders? AIDS 28, 493–501 (2014).

    Article  CAS  PubMed  Google Scholar 

  66. Ellis, R. J. et al. Randomized trial of central nervous system-targeted antiretrovirals for HIV-associated neurocognitive disorder. Clin. Infect. Dis. 58, 1015–1022 (2014).

    Article  CAS  PubMed  Google Scholar 

  67. Cusini, A. et al. Higher CNS penetration-effectiveness of long-term combination antiretroviral therapy is associated with better HIV-1 viral suppression in cerebrospinal fluid. J. Acquir. Immune Defic. Syndr. 62, 28–35 (2013).

    Article  CAS  PubMed  Google Scholar 

  68. Ciccarelli, N. et al. Revised central nervous system neuropenetration-effectiveness score is associated with cognitive disorders in HIV-infected patients with controlled plasma viraemia. Antivir. Ther. 18, 153–160 (2013).

    Article  PubMed  Google Scholar 

  69. Walker, D. K. et al. Preclinical assessment of the distribution of maraviroc to potential human immunodeficiency virus (HIV) sanctuary sites in the central nervous system (CNS) and gut-associated lymphoid tissue (GALT). Xenobiotica 38, 1330–1339 (2008).

    Article  CAS  PubMed  Google Scholar 

  70. Yilmaz, A., Watson, V., Else, L. & Gisslèn, M. Cerebrospinal fluid maraviroc concentrations in HIV-1 infected patients. AIDS 23, 2537–2540 (2009).

    Article  CAS  PubMed  Google Scholar 

  71. Tiraboschi, J. M., Niubo, J., Curto, J. & Podzamczer, D. Maraviroc concentrations in cerebrospinal fluid in HIV-infected patients. J. Acquir. Immune Defic. Syndr. 55, 606–609 (2010).

    Article  CAS  PubMed  Google Scholar 

  72. Croteau, D. et al. Lower than expected maraviroc concentrations in cerebrospinal fluid exceed the wild-type CC chemokine receptor 5-tropic HIV-1 50% inhibitory concentration. AIDS 26, 890–893 (2012).

    Article  CAS  PubMed  Google Scholar 

  73. Garvey, L. et al. CNS effects of a CCR5 inhibitor in HIV-infected subjects: a pharmacokinetic and cerebral metabolite study. J. Antimicrob. Chemother. 67, 206–212 (2012).

    Article  CAS  PubMed  Google Scholar 

  74. Melica, G. et al. Maraviroc-containing regimen suppresses HIV replication in the cerebrospinal fluid of patients with neurological symptoms. AIDS 24, 2130–2133 (2010).

    Article  PubMed  Google Scholar 

  75. Kelly, K. M. et al. Neuroprotective maraviroc monotherapy in simian immunodeficiency virus-infected macaques: reduced replicating and latent SIV in the brain. AIDS 27, F21–F28 (2013).

    Article  CAS  PubMed  Google Scholar 

  76. Roberts, D. J. et al. Effect of acute inflammatory brain injury on accumulation of morphine and morphine 3- and 6-glucuronide in the human brain. Crit. Care Med. 37, 2767–2774 (2009).

    CAS  PubMed  Google Scholar 

  77. Reshef, R. et al. Blockade of lymphocyte chemotaxis in visceral graft-versus-host disease. N. Engl. J. Med. 367, 135–145 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Murai, M. et al. Active participation of CCR5+CD8+ T lymphocytes in the pathogenesis of liver injury in graft-versus-host disease. J. Clin. Invest. 104, 49–57 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Fleishaker, D. L. et al. Maraviroc, a chemokine receptor-5 antagonist, fails to demonstrate efficacy in the treatment of patients with rheumatoid arthritis in a randomized, double-blind placebo-controlled trial. Arthritis Res. Ther. 14, R11 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Ben-Nun, A. et al. From classic to spontaneous and humanized models of multiple sclerosis: impact on understanding pathogenesis and drug development. J. Autoimmun. 54, 33–50 (2014).

    Article  CAS  PubMed  Google Scholar 

  81. Sato, W. et al. CCR2+CCR5+ T cells produce matrix metalloproteinase-9 and osteopontin in the pathogenesis of multiple sclerosis. J. Immunol. 189, 5057–5065 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Balashov, K. E., Rottman, J. B., Weiner, H. L. & Hancock, W. W. CCR5+ and CXCR3+ T cells are increased in multiple sclerosis and their ligands MIP-1α and IP-10 are expressed in demyelinating brain lesions. Proc. Natl Acad. Sci. USA 96, 6873–6878 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Sørensen, T. L. et al. Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients. J. Clin. Invest. 103, 807–815 (1999).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Ni, J. et al. The chemokine receptor antagonist, TAK-779, decreased experimental autoimmune encephalomyelitis by reducing inflammatory cell migration into the central nervous system, without affecting T cell function. Br. J. Pharmacol. 158, 2046–2056 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Trebst, C. et al. CCR1+/CCR5+ mononuclear phagocytes accumulate in the central nervous system of patients with multiple sclerosis. Am. J. Pathol. 159, 1701–1710 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Glabinski, A. R., Tani, M., Strieter, R. M., Tuohy, V. K. & Ransohoff, R. M. Synchronous synthesis of α- and β-chemokines by cells of diverse lineage in the central nervous system of mice with relapses of chronic experimental autoimmune encephalomyelitis. Am. J. Pathol. 150, 617–630 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Miyagishi, R., Kikuchi, S., Takayama, C., Inoue, Y. & Tashiro, K. Identification of cell types producing RANTES, MIP-1α and MIP-1β in rat experimental autoimmune encephalomyelitis by in situ hybridization. J. Neuroimmunol. 77, 17–26 (1997).

    Article  CAS  PubMed  Google Scholar 

  88. Simpson, J. E., Newcombe, J., Cuzner, M. L. & Woodroofe, M. N. Expression of monocyte chemoattractant protein-1 and other β-chemokines by resident glia and inflammatory cells in multiple sclerosis lesions. J. Neuroimmunol. 84, 238–249 (1998).

    Article  CAS  PubMed  Google Scholar 

  89. Boven, L. A., Montagne, L., Nottet, H. S. & De Groot, C. J. Macrophage inflammatory protein-1α (MIP-1α), MIP-1β, and RANTES mRNA semiquantification and protein expression in active demyelinating multiple sclerosis (MS) lesions. Clin. Exp. Immunol. 122, 257–263 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Zheng, H. M., Jiang, Y., Wang, J. R., Gong, X. L. & Guo, B. Y. Mimic peptides bonding specifically with the first and second extracellular loops of the CC chemokine receptor 5 derived from a phage display peptide library are potent inhibitors of experimental autoimmune encephalomyelitis. Inflamm. Res. 60, 759–767 (2011).

    Article  CAS  PubMed  Google Scholar 

  91. Glass, W. G. et al. Antibody targeting of the CC chemokine ligand 5 results in diminished leukocyte infiltration into the central nervous system and reduced neurologic disease in a viral model of multiple sclerosis. J. Immunol. 172, 4018–4025 (2004).

    Article  CAS  PubMed  Google Scholar 

  92. Kennedy, K. J., Strieter, R. M., Kunkel, S. L., Lukacs, N. W. & Karpus, W. J. Acute and relapsing experimental autoimmune encephalomyelitis are regulated by differential expression of the CC chemokines macrophage inflammatory protein-1α and monocyte chemotactic protein-1. J. Neuroimmunol. 92, 98–108 (1998).

    Article  CAS  PubMed  Google Scholar 

  93. Youssef, S. et al. Long-lasting protective immunity to experimental autoimmune encephalomyelitis following vaccination with naked DNA encoding C-C chemokines. J. Immunol. 161, 3870–3879 (1998).

    CAS  PubMed  Google Scholar 

  94. Karpus, W. J. et al. An important role for the chemokine macrophage inflammatory protein-1α in the pathogenesis of the T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis. J. Immunol. 155, 5003–5010 (1995).

    CAS  PubMed  Google Scholar 

  95. Sapir, Y. et al. A fusion protein encoding the second extracellular domain of CCR5 arrests chemokine-induced cosignaling and effectively suppresses ongoing experimental autoimmune encephalomyelitis. J. Immunol. 185, 2589–2599 (2010).

    Article  CAS  PubMed  Google Scholar 

  96. Tran, E. H., Kuziel, W. A. & Owens, T. Induction of experimental autoimmune encephalomyelitis in C57BL/6 mice deficient in either the chemokine macrophage inflammatory protein-1α or its CCR5 receptor. Eur. J. Immunol. 30, 1410–1415 (2000).

    Article  CAS  PubMed  Google Scholar 

  97. Kantarci, O. H. et al. CCR5Δ32 polymorphism effects on CCR5 expression, patterns of immunopathology and disease course in multiple sclerosis. J. Neuroimmunol. 169, 137–143 (2005).

    Article  CAS  PubMed  Google Scholar 

  98. Silversides, J. A., Heggarty, S. V., McDonnell, G. V., Hawkins, S. A. & Graham, C. A. Influence of CCR5 δ32 polymorphism on multiple sclerosis susceptibility and disease course. Mult. Scler. 10, 149–152 (2004).

    Article  CAS  PubMed  Google Scholar 

  99. Sellebjerg, F., Madsen, H. O., Jensen, C. V., Jensen, J. & Garred, P. CCR5 Δ32, matrix metalloproteinase-9 and disease activity in multiple sclerosis. J. Neuroimmunol. 102, 98–106 (2000).

    Article  CAS  PubMed  Google Scholar 

  100. van Veen, T. et al. CCL5 and CCR5 genotypes modify clinical, radiological and pathological features of multiple sclerosis. J. Neuroimmunol. 190, 157–164 (2007).

    Article  CAS  PubMed  Google Scholar 

  101. Møller, M. et al. The chemokine receptor CCR5 Δ32 allele in natalizumab-treated multiple sclerosis. Acta Neurol. Scand. 129, 27–31 (2014).

    Article  PubMed  CAS  Google Scholar 

  102. Varadkar, S. et al. Rasmussen's encephalitis: clinical features, pathobiology, and treatment advances. Lancet Neurol. 13, 195–205 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Bien, C. G. et al. Destruction of neurons by cytotoxic T cells: a new pathogenic mechanism in Rasmussen's encephalitis. Ann. Neurol. 51, 311–318 (2002).

    Article  CAS  PubMed  Google Scholar 

  104. Bauer, J. et al. Astrocytes are a specific immunological target in Rasmussen's encephalitis. Ann. Neurol. 62, 67–80 (2007).

    Article  PubMed  Google Scholar 

  105. Schwab, N. et al. CD8+ T-cell clones dominate brain infiltrates in Rasmussen encephalitis and persist in the periphery. Brain 132, 1236–1246 (2009).

    Article  PubMed  Google Scholar 

  106. Kossoff, E. H. et al. Hemispherectomy for intractable unihemispheric epilepsy etiology versus outcome. Neurology 61, 887–890 (2003).

    Article  CAS  PubMed  Google Scholar 

  107. Bien, C. G. et al. Rasmussen encephalitis: incidence and course under randomized therapy with tacrolimus or intravenous immunoglobulins. Epilepsia 54, 543–550 (2013).

    Article  CAS  PubMed  Google Scholar 

  108. Sierra-Madero, J. G. et al. Effect of the CCR5 antagonist maraviroc on the occurrence of immune reconstitution inflammatory syndrome in HIV (CADIRIS): a double-blind, randomised, placebo-controlled trial. Lancet HIV 1, e60–e67 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Martin-Blondel, G. et al. Is maraviroc beneficial in paradoxical progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome management? AIDS 23, 2545–2546 (2009).

    Article  PubMed  Google Scholar 

  110. Martin-Blondel, G. et al. Pathogenesis of the immune reconstitution inflammatory syndrome affecting the central nervous system in patients infected with HIV. Brain 134, 928–946 (2011).

    Article  PubMed  Google Scholar 

  111. Giacomini, P. S. et al. Maraviroc and JC virus-associated immune reconstitution inflammatory syndrome. N. Engl. J. Med. 370, 486–488 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Martin-Blondel, G. et al. Therapeutic use of CCR5 antagonists is supported by strong expression of CCR5 on CD8+ T cells in progressive multifocal leukoencephalopathy-associated immune reconstitution inflammatory syndrome. Acta Neuropathol. 129, 463–465 (2015).

    Article  PubMed  Google Scholar 

  113. Tan, I. L., McArthur, J. C., Clifford, D. B., Major, E. O. & Nath, A. Immune reconstitution inflammatory syndrome in natalizumab-associated PML. Neurology 77, 1061–1067 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Vermersch, P. et al. Clinical outcomes of natalizumab-associated progressive multifocal leukoencephalopathy. Neurology 76, 1697–1704 (2011).

    Article  CAS  PubMed  Google Scholar 

  115. Stork, L., Brück, W., Bar-Or, A. & Metz, I. High CCR5 expression in natalizumab-associated progressive multifocal leukoencephalopathy immune reconstitution inflammatory syndrome supports treatment with the CCR5 inhibitor maraviroc. Acta Neuropathol. 129, 467–468 (2015).

    Article  PubMed  Google Scholar 

  116. Glass, W. G. et al. Chemokine receptor CCR5 promotes leukocyte trafficking to the brain and survival in West Nile virus infection. J. Exp. Med. 202, 1087–1098 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Huffnagle, G. B. et al. Cutting edge: role of C-C chemokine receptor 5 in organ-specific and innate immunity to Cryptococcus neoformans. J. Immunol. 163, 4642–4646 (1999).

    CAS  PubMed  Google Scholar 

  118. Khan, I. A. et al. CCR5 is essential for NK cell trafficking and host survival following Toxoplasma gondii infection. PLoS Pathog. 2, e49 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Larena, M., Regner, M. & Lobigs, M. The chemokine receptor CCR5, a therapeutic target for HIV/AIDS antagonists, is critical for recovery in a mouse model of Japanese encephalitis. PLoS ONE 7, e44834 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Glass, W. G. et al. CCR5 deficiency increases risk of symptomatic West Nile virus infection. J. Exp. Med. 203, 35–40 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Lim, J. K. et al. Genetic deficiency of chemokine receptor CCR5 is a strong risk factor for symptomatic West Nile virus infection: a meta-analysis of 4 cohorts in the US epidemic. J. Infect. Dis. 197, 262–265 (2008).

    Article  PubMed  Google Scholar 

  122. Lim, J. K. et al. CCR5 deficiency is a risk factor for early clinical manifestations of West Nile virus infection but not for viral transmission. J. Infect. Dis. 201, 178–185 (2010).

    Article  CAS  PubMed  Google Scholar 

  123. Kindberg, E. et al. A deletion in the chemokine receptor 5 (CCR5) gene is associated with tickborne encephalitis. J. Infect. Dis. 197, 266–269 (2008).

    Article  CAS  PubMed  Google Scholar 

  124. Mickienė, A. et al. Polymorphisms in chemokine receptor 5 and Toll-like receptor 3 genes are risk factors for clinical tick-borne encephalitis in the Lithuanian population. PLoS ONE 9, e106798 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Barkhash, A. V., Voevoda, M. I. & Romaschenko, A. G. Association of single nucleotide polymorphism rs3775291 in the coding region of the TLR3 gene with predisposition to tick-borne encephalitis in a Russian population. Antiviral Res. 99, 136–138 (2013).

    Article  CAS  PubMed  Google Scholar 

  126. Pulendran, B. et al. Case of yellow fever vaccine-associated viscerotropic disease with prolonged viremia, robust adaptive immune responses, and polymorphisms in CCR5 and RANTES genes. J. Infect. Dis. 198, 500–507 (2008).

    Article  PubMed  Google Scholar 

  127. Nansen, A. et al. The role of CC chemokine receptor 5 in antiviral immunity. Blood 99, 1237–1245 (2002).

    Article  CAS  PubMed  Google Scholar 

  128. Zhong, M. X., Kuziel, W. A., Pamer, E. G. & Serbina, N. V. Chemokine receptor 5 is dispensable for innate and adaptive immune responses to Listeria monocytogenes infection. Infect. Immun. 72, 1057–1064 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Silva, A. A. et al. Trypanosoma cruzi-triggered meningoencephalitis is a CCR1/CCR5-independent inflammatory process. J. Neuroimmunol. 184, 156–163 (2007).

    Article  CAS  PubMed  Google Scholar 

  130. Sarfo, B. Y. et al. The cerebral-malaria-associated expression of RANTES, CCR3 and CCR5 in post-mortem tissue samples. Ann. Trop. Med. Parasitol. 98, 297–303 (2004).

    Article  CAS  PubMed  Google Scholar 

  131. Belnoue, E. et al. CCR5 deficiency decreases susceptibility to experimental cerebral malaria. Blood 101, 4253–4259 (2003).

    Article  CAS  PubMed  Google Scholar 

  132. McManus, C. M. et al. Chemokine and chemokine-receptor expression in human glial elements: induction by the HIV protein, Tat, and chemokine autoregulation. Am. J. Pathol. 156, 1441–1453 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Albright, A. V. et al. Microglia express CCR5, CXCR4, and CCR3, but of these, CCR5 is the principal coreceptor for human immunodeficiency virus type 1 dementia isolates. J. Virol. 73, 205–213 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Spudich, S. S. et al. HIV-1 chemokine coreceptor utilization in paired cerebrospinal fluid and plasma samples: a survey of subjects with viremia. J. Infect. Dis. 191, 890–898 (2005).

    Article  CAS  PubMed  Google Scholar 

  135. Shacklett, B. L. et al. Increased adhesion molecule and chemokine receptor expression on CD8+ T cells trafficking to cerebrospinal fluid in HIV-1 infection. J. Infect. Dis. 189, 2202–2212 (2004).

    Article  CAS  PubMed  Google Scholar 

  136. Gramegna, P. et al. In vitro downregulation of matrix metalloproteinase-9 in rat glial cells by CCR5 antagonist maraviroc: therapeutic implication for HIV brain infection. PLoS ONE 6, e28499 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Maung, R. et al. CCR5 knockout prevents neuronal injury and behavioral impairment induced in a transgenic mouse model by a CXCR4-using HIV-1 glycoprotein 120. J. Immunol. 193, 1895–1910 (2014).

    Article  CAS  PubMed  Google Scholar 

  138. Tiraboschi, J. et al. Viral and inflammatory markers in cerebrospinal fluid of patients with HIV-1-associated neurocognitive impairment during antiretroviral treatment switch. HIV Med. 16, 388–392 (2015).

    Article  CAS  PubMed  Google Scholar 

  139. Ndhlovu, L. C. et al. Treatment intensification with maraviroc (CCR5 antagonist) leads to declines in CD16-expressing monocytes in cART-suppressed chronic HIV-infected subjects and is associated with improvements in neurocognitive test performance: implications for HIV-associated neurocognitive disease (HAND). J. Neurovirol. 20, 571–582 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Bernal, F. et al. Immunohistochemical analysis of anti-Hu-associated paraneoplastic encephalomyelitis. Acta Neuropathol. 103, 509–515 (2002).

    Article  CAS  PubMed  Google Scholar 

  141. Bien, C. G. et al. Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis. Brain 135, 1622–1638 (2012).

    Article  PubMed  Google Scholar 

  142. Pignolet, B. S., Gebauer, C. M. & Liblau, R. S. Immunopathogenesis of paraneoplastic neurological syndromes associated with anti-Hu antibodies: a beneficial antitumor immune response going awry. Oncoimmunology 2, e27384 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Saita, Y., Kondo, M. & Shimizu, Y. Species selectivity of small-molecular antagonists for the CCR5 chemokine receptor. Int. Immunopharmacol. 7, 1528–1534 (2007).

    Article  CAS  PubMed  Google Scholar 

  144. Sorce, S., Myburgh, R. & Krause, K. H. The chemokine receptor CCR5 in the central nervous system. Prog. Neurobiol. 93, 297–311 (2011).

    Article  CAS  PubMed  Google Scholar 

  145. Oppermann, M. Chemokine receptor CCR5: insights into structure, function, and regulation. Cell. Signal. 16, 1201–1210 (2004).

    Article  CAS  PubMed  Google Scholar 

  146. Gheuens, S., Wüthrich, C. & Koralnik, I. J. Progressive multifocal leukoencephalopathy: why gray and white matter. Annu. Rev. Pathol. 8, 189–215 (2013).

    Article  CAS  PubMed  Google Scholar 

  147. Müller, M. et al. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lancet Infect. Dis. 10, 251–261 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  148. Martin-Blondel, G. et al. In situ evidence of JC virus control by CD8+ T cells in PML-IRIS during HIV infection. Neurology 81, 964–970 (2013).

    Article  CAS  PubMed  Google Scholar 

  149. Metz, I. et al. Pathology of immune reconstitution inflammatory syndrome in multiple sclerosis with natalizumab-associated progressive multifocal leukoencephalopathy. Acta Neuropathol. 123, 235–245 (2012).

    Article  CAS  PubMed  Google Scholar 

  150. Tan, K., Roda, R., Ostrow, L., McArthur, J. & Nath, A. PML-IRIS in patients with HIV infection: clinical manifestations and treatment with steroids. Neurology 72, 1458–1464 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Clifford, D. B. et al. Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol. 9, 438–446 (2010).

    Article  CAS  PubMed  Google Scholar 

  152. Antoniol, C. et al. Impairment of JCV-specific T-cell response by corticotherapy: effect on PML-IRIS management? Neurology 79, 2258–2264 (2012).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors' work is supported by the French Institute of Health and Medical Research, The French National Center for Scientific Research, Toulouse III University Midi-Pyrénées Region, ARSEP foundation and The French National Research Agency. R.S.L. is also supported by a grant from the European Union (FP7-PEOPLE-2012-ITN NeuroKine). The funding sources had no role in the writing of the manuscript or the decision to submit it for publication. We thank Dr H. Dumas for his help on brain MRI analysis of patients with PML-IRIS, and Dr D. Dunia for insightful comments on the manuscript.

Author information

Authors and Affiliations

  1. Department of Infectious and Tropical Diseases, Toulouse University Hospital, Place du Docteur Baylac, TSA 40031, 31059, Toulouse cedex 9, France

    Guillaume Martin-Blondel

  2. INSERM U1043, CNRS UMR 5282, Centre de Physiopathologie Toulouse-Purpan, Purpan Hospital, BP 3028, 31024, Toulouse cedex 3, France

    Guillaume Martin-Blondel, David Brassat & Roland S. Liblau

  3. Department of Neurology, Pole des Neurosciences, Toulouse University Hospital, Place du Docteur Baylac TSA 40031, 31059, Toulouse cedex 9, France

    David Brassat

  4. Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090, Vienna, Austria

    Jan Bauer & Hans Lassmann

Authors
  1. Guillaume Martin-Blondel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David Brassat
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jan Bauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hans Lassmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Roland S. Liblau
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

G.M.-B. and R.L. wrote the article. All authors researched data for the article, made substantial contributions to discussion of the content, and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Guillaume Martin-Blondel.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Martin-Blondel, G., Brassat, D., Bauer, J. et al. CCR5 blockade for neuroinflammatory diseases — beyond control of HIV. Nat Rev Neurol 12, 95–105 (2016). https://doi.org/10.1038/nrneurol.2015.248

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneurol.2015.248

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing