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Neuroprotective maraviroc monotherapy in simian immunodeficiency virus-infected macaques: reduced replicating and latent SIV in the brain

Kelly, Kathleen M.a; Beck, Sarah E.a; Pate, Kelly A. Metcalfa; Queen, Suzanne E.a; Dorsey, Jamie L.a; Adams, Robert J.a; Avery, Lindsay B.b; Hubbard, Walterc; Tarwater, Patrick M.d; Mankowski, Joseph L.a,e,f

doi: 10.1097/QAD.0000000000000074
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Objective: HIV-associated neurocognitive deficits remain a challenge despite suppressive combined antiretroviral therapy. Given the association between HIV-induced central nervous system (CNS) disease and replication of HIV in immune-activated macrophages, CCR5 antagonists may attenuate CNS disease by modulating inflammatory signaling and by limiting viral replication.

Design: To establish whether initiating CCR5 inhibition during early infection altered CNS disease progression, outcomes were compared between simian immunodeficiency virus (SIV)-infected macaques treated with maraviroc (MVC) versus untreated SIV-infected macaques.

Methods: Six SIV-infected rhesus macaques were treated with MVC monotherapy for 5 months beginning 24 days postinoculation; 22 SIV-infected animals served as untreated controls. SIV RNA levels in plasma, cerobrospinal fluid, and brain, and CNS expression of TNFα and CCL2 were measured by qRT-PCR. Immunostaining for CD68 and amyloid precursor protein in the brain was measured by image analysis. Plasma sCD163 was measured by ELISA.

Results: SIV RNA and proviral DNA levels in brain were markedly lower with MVC treatment, demonstrating CCR5 inhibition reduces CNS replication of SIV and may reduce the CNS latent viral reservoir. MVC treatment also lowered monocyte and macrophage activation, represented by CNS CD68 immunostaining and plasma sCD163 levels, and reduced both TNFα and CCL2 RNA expression in brain. Treatment also reduced axonal amyloid precursor protein immunostaining to levels present in uninfected animals, consistent with neuroprotection.

Conclusion: CCR5 inhibitors may prevent neurologic disorders in HIV-infected individuals by reducing inflammation and by limiting viral replication in the brain. Furthermore, CCR5 inhibitors may reduce the latent viral reservoir in the CNS. Adding CCR5 inhibitors to combined antiretroviral regimens may offer multiple neuroprotective benefits.

aDepartment of Molecular and Comparative Pathobiology

bDepartment of Pharmacology and Molecular Sciences

cDivision of Clinical Pharmacology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland

dDepartment of Biostatistics, Texas Tech University School of Medicine, El Paso Texas

eDepartment of Neurology

fDepartment of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Correspondence to Dr Joseph L. Mankowski, Department of Molecular and Comparative Pathobiology, Johns Hopkins University, 733 N. Broadway, BRB 827, Baltimore, MD 21205-2196, USA.

Data was presented in part at the 18th CROI Conference on Retroviruses and Opportunistic Infections, 2011, Boston, Massachusetts, USA.

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivitives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/3.0.

Received September 3, 2013

Accepted September 12, 2013

© 2013 Lippincott Williams & Wilkins, Inc.