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

Objective: HIV-associated neurocognitive deficits remain a challenge despite suppressive combined anti-retroviral therapy. Given the association between HIV-induced 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 SIV-infected macaques treated with maraviroc versus untreated SIV-infected macaques. Methods: Six SIV-infected rhesus macaques were treated with maraviroc monotherapy for 5 months beginning 24 days post-inoculation; 22 SIV-infected animals served as untreated controls. SIV RNA levels in plasma, CSF, and brain, and CNS expression of TNFa 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 maraviroc-treatment, demonstrating CCR5 inhibition reduces CNS replication of SIV and may reduce the CNS latent viral reservoir. Maraviroc-treatment also lowered monocyte and macrophage activation, represented by CNS CD68 immunostaining and plasma sCD163 levels, and reduced both TNFaand 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