Ccr5 blockade for neuroinflammatory diseases — beyond control of hiv

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. Access

through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal

Receive 12 print issues and online access $209.00 per year only $17.42 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices

may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support

SIMILAR CONTENT BEING VIEWED BY OTHERS A NOVEL SMALL-MOLECULAR CCR5 ANTAGONIST PROMOTES NEURAL REPAIR AFTER STROKE Article 17 May 2023 THINKING OUTSIDE THE BOX: NON-CANONICAL TARGETS IN

MULTIPLE SCLEROSIS Article 06 June 2022 CKD-506: A NOVEL HDAC6-SELECTIVE INHIBITOR THAT EXERTS THERAPEUTIC EFFECTS IN A RODENT MODEL OF MULTIPLE SCLEROSIS Article Open access 14 July 2021

REFERENCES * 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  * 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  * 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  * Luther, S. A. & Cyster, J. G. Chemokines as regulators of T cell differentiation. _Nat.

Immunol._ 2, 102–107 (2001). Article  CAS  PubMed  Google Scholar  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * Molon, B. _ et al_. T cell costimulation by chemokine receptors. _Nat. Immunol._ 6, 465–471 (2005). Article  CAS  PubMed  Google

Scholar  * 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  * 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  * Sheridan, B. S. & Lefrançois, L. Regional and mucosal memory T cells. _Nat. Immunol._ 12, 485–491 (2011). Article  CAS  PubMed 

PubMed Central  Google Scholar  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * Ioannidis, J. P. _ et al_. Effects of _CCR5_-Δ_32_,

_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  * 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  * 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  * 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  *

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  *

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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  *

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  *

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  * 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  * 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  * 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  * Clifford, D.

B. & Ances, B. M. HIV-associated neurocognitive disorder. _Lancet Infect. Dis._ 13, 976–986 (2013). Article  PubMed  PubMed Central  Google Scholar  * 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  * 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  * Letendre, S. Central nervous system complications in HIV disease: HIV-associated neurocognitive disorder.

_Top. Antivir. Med._ 19, 137–142 (2011). PubMed  Google Scholar  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  *

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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  *

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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  *

Bauer, J. _ et al_. Astrocytes are a specific immunological target in Rasmussen's encephalitis. _Ann. Neurol._ 62, 67–80 (2007). Article  PubMed  Google Scholar  * 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  * Kossoff, E. H. _ et

al_. Hemispherectomy for intractable unihemispheric epilepsy etiology versus outcome. _Neurology_ 61, 887–890 (2003). Article  CAS  PubMed  Google Scholar  * 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  *

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  * 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  * 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  * 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  * 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  * 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  * Vermersch, P. _ et al_. Clinical outcomes of natalizumab-associated progressive multifocal leukoencephalopathy. _Neurology_ 76, 1697–1704 (2011). Article  CAS  PubMed  Google

Scholar  * 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  * 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  *

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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * Nansen, A. _ et al_. The role of CC chemokine receptor 5 in antiviral

immunity. _Blood_ 99, 1237–1245 (2002). Article  CAS  PubMed  Google Scholar  * 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  * 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  * 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  * Belnoue, E. _ et al_. CCR5 deficiency decreases susceptibility to experimental cerebral malaria. _Blood_ 101, 4253–4259 (2003). Article  CAS  PubMed  Google Scholar  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * Bernal, F. _ et al_. Immunohistochemical analysis of anti-Hu-associated paraneoplastic

encephalomyelitis. _Acta Neuropathol._ 103, 509–515 (2002). Article  CAS  PubMed  Google Scholar  * Bien, C. G. _ et al_. Immunopathology of autoantibody-associated encephalitides: clues for

pathogenesis. _Brain_ 135, 1622–1638 (2012). Article  PubMed  Google Scholar  * 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  * 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  * 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 

* Oppermann, M. Chemokine receptor CCR5: insights into structure, function, and regulation. _Cell. Signal._ 16, 1201–1210 (2004). Article  CAS  PubMed  Google Scholar  * 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  *

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  * 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  * 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  * 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  * 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  * 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 * Department of

Infectious and Tropical Diseases, Toulouse University Hospital, Place du Docteur Baylac, TSA 40031, 31059, Toulouse cedex 9, France Guillaume Martin-Blondel * 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 * Department of

Neurology, Pole des Neurosciences, Toulouse University Hospital, Place du Docteur Baylac TSA 40031, 31059, Toulouse cedex 9, France David Brassat * Center for Brain Research, Medical

University of Vienna, Spitalgasse 4, A-1090, Vienna, Austria Jan Bauer & Hans Lassmann Authors * Guillaume Martin-Blondel View author publications You can also search for this author

inPubMed Google Scholar * David Brassat View author publications You can also search for this author inPubMed Google Scholar * Jan Bauer View author publications You can also search for this

author inPubMed Google Scholar * Hans Lassmann View author publications You can also search for this author inPubMed Google Scholar * Roland S. Liblau View author publications You can also

search for this author inPubMed 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 POWERPOINT SLIDE FOR FIG. 1 POWERPOINT SLIDE FOR FIG. 2 POWERPOINT SLIDE FOR FIG. 3 RIGHTS AND PERMISSIONS Reprints and

permissions ABOUT THIS ARTICLE 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: 18 January 2016 * Issue Date: February 2016 * DOI: https://doi.org/10.1038/nrneurol.2015.248 SHARE

THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to

clipboard Provided by the Springer Nature SharedIt content-sharing initiative