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)

Abstract

HIV-associated neurocognitive disorders (HAND) continues to be prevalent (30–50 %) despite plasma HIVRNA suppression with combination antiretroviral therapy (cART). There is no proven therapy for individuals on suppressive cARTwith HAND. We have shown that the degree of HIV reservoir burden (HIV DNA) in monocytes appear to be linked to cognitive outcomes. HIV infection of monocytes may therefore be critical in the pathogenesis of HAND. A single arm, open-labeled trial was conducted to examine the effect of maraviroc (MVC) intensification on monocyte inflammation and neuropsychological (NP) performance in 15 HIV subjects on stable 6-month cART with undetectable plasma HIV RNA (<48 copies/ml) and detectable monocyte HIV DNA (>10 copies/106 cells). MVC was added to their existing cART regimen for 24 weeks. Post-intensification change in monocytes was assessed using multiparametric flow cytometry, monocyte HIV DNA content by PCR, soluble CD163 (sCD163) by an ELISA, and NP performance over 24 weeks. In 12 evaluable subjects, MVC intensification resulted in a decreased proportion of circulating intermediate (median; 3.06 % (1.93, 6.45) to 1.05 % (0.77, 2.26)) and nonclassical (5.2 % (3.8, 7.9) to 3.2 % (1.8, 4.8)) CD16-expressing monocytes, a reduction in monocyte HIV DNA content to zero log10 copies/106 cells and in levels of sCD163 of 43 % by 24 weeks. This was associated with significant improvement in NP performance among six subjects who entered the study with evidence of mild to moderate cognitive impairment. The results of this study suggest that antiretroviral therapy with potency against monocytes may have efficacy against HAND.

Neurocognition with maraviroc compared with tenofovir in HIV

“…In a rat model, CCR5 inhibition downregulated proinflammatory matrix metalloproteinase-9 [11], and in a macaque model MVC reduced replicating and latent Simian Immunodeficiency Virus (SIV) as well as monocyte and macrophage activation in the brain [12]. Small clinical studies in HIV-1 infected individuals have also suggested that intensifying ART with MVC may improve neuronal integrity [13] or neurocognitive performance [14]. On the other hand, CCR5 deficiency has been associated with worse outcomes during CNS viral infections [15, 16], and an animal study reported increased microglial activation with MVC, suggesting the possibility of exacerbating neuronal pathology with chronic MVC use [17].…”

Strategies to target non-T-cell HIV reservoirs

“…Both Maraviroc and Raltegravir have been tested under cART intensification. We have shown that intensification with Maraviroc for 24 weeks in HIV-infected cART treated participants leads to a reduction in monocyte HIV DNA 36 . Lafeuillade et al showed that from 10 PBMC and gut biopsy samples of HIV-infected patients on either Truvada® or Kaletra® with further intensified antiretroviral therapy by taking Maraviroc and Raltegravir showed no appreciable proviral DNA reservoir reduction in blood or gut biopsies, except in a few patient cases where proviral DNA in gut biopsies showed a modest reduction 37 .…”

Central nervous system-penetrating antiretrovirals impair energetic reserve in striatal nerve terminals

“…7). Interestingly, maraviroc has shown preliminary beneficial effects on cognition in HAND (Gates et al , 2016; Ndhlovu et al , 2014), and clinical trials using maraviroc for HAND are underway (ClinicalTrials.gov Identifiers NCT02159027 and NCT02519777), under the hypothesis that such treatment will be beneficial to neuropsychological/neurocognitive performance. Such studies will help ascertain the true effects of maraviroc on the CNS in HAND.…”