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 HIV-RNA suppression with combination antiretroviral therapy (cART). There is no proven therapy for individuals on suppressive cART with 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/10(6) 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/10(6) 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.

Fig. 1

Flow cytometric gating strategy to assess changes in monocyte subset frequencies (a). Representative gating strategy of single-cell multiparametric flow cytometry assessment of monocytes subsets based on CD14 and CD16 expression among live HLA-DR-expressing PBMC that excluded Tcells, B cells, and NK cells. HLA-DR expression intensity on the three monocyte subsets is represented in the histogram (a). The plots depict changes in frequency of classical (b, e), intermediate (c, f), and nonclassical (d, g) monocyte subsets in all study subjects (b–d) or stratified by cognitive status (e–g). The data were analyzed in 12 subjects before and during 24 weeks of MVC intensification. Graphs depict the change in CD14 and CD16 expression on HLA-DR monocytes, plotted with the medians and interquartile ranges for weeks 0, 4, 12, and 24. The p values are provided for the changes in monocyte subsets from week 0 to each indicated week. Median levels at weeks 0, 4, 12, and 24 are plotted with interquartile ranges, and p values are provided Wilcoxon signed-rank tests for the changes from week 0 to each indicated week

Fig. 2

Flow cytometric gating strategy to assess changes in Tcell subset frequencies Representative gating strategy of single-cell flow cytometry assessment of live CD3+ CD8+ T subsets based on a CD38 and HLA-DR expression. The data were analyzed in 12 subjects before and during 24 weeks of MVC intensification. Graphs depict the change in CD38 and HLA-DR expression on CD8+ T cells plotted with the medians and interquartile ranges for weeks 0, 4, 12, and 24 in the group as a whole (b, c) or stratified based on cognitive status (n=6 each) (d, e). The p values are provided for the changes in T cell activation from week 0 to each indicated week. Median levels at weeks 0, 4, 12, and 24 are plotted with interquartile ranges, and p values are provided Wilcoxon-signed rank tests for the changes from week 0 to each indicated week

Fig. 3

Change in plasma levels of sCD163 at entry (week 0) and weeks 4, 12, and 24 of MVC intensification plasma levels of sCD163 were analyzed using the Wilcoxon signed-rank test and are plotted showing the median and interquartile ranges in the group (a) or separated based on cognitive status. The p values are depicted for the changes in sCD163 levels from week 0 to each indicated week

Fig. 4

Change in monocyte HIV DNA content at entry (week 0) and weeks 4, 12, and 24 of MVC intensification. This graph depicts the change in DNA content on a log₁₀ scale, plotted with the medians and interquartile ranges for weeks 0, 4, 12, and 24 in all study subjects (a) or separated based on cognitive status (b). The p values are provided for the changes in HIV DNA from week 0 to each indicated week