Intact HIV Reservoir in Monocytes Is Associated With Cognitive Function in Virally Suppressed Women With HIV

Abstract

Background: Monocytes are susceptible to human immunodeficiency virus (HIV) infection, form HIV reservoirs, and contribute to central nervous system complications (eg, cognitive impairment) in virally suppressed women with HIV (vsWWH). However, it remains unknown if the quality and/or quantity of the monocyte reservoir contributes to cognition in vsWWH.

Methods: Sixty-two vsWWH (mean age = 56.1 years, SD = 7.1; 93% Black, non-Hispanic; all HIV RNA <250 copies/mL) completed a cognitive test battery, blood draw, and whole-blood immunophenotyping. Monocytes and CD4 T cells were isolated from a subset of 53 participants and the HIV reservoir was assessed using cell-specific intact proviral DNA assays (IPDA). Demographically adjusted z-scores were calculated for each outcome using data from participants without HIV in the Women's Interagency HIV Study. Cognitive outcomes of interest included domain-specific and global z-scores.

Results: Thirty-Eight percent of vsWWH had detectable intact HIV genomes in monocytes (median = 21.5 copies/million). Higher levels of intact HIV genomes per million monocytes were associated with poorer verbal memory (delayed recall, r = 0.55, P = .01; recognition, r = 0.46, P = .04), fine motor skills (r = 0.50, P = .03), and global function (r = 0.47, P = .04). Higher levels of intact HIV genomes in monocytes were associated with percent intermediate monocytes (r = 0.60, P = .008), and the ratio of intact per intermediate monocyte was associated with worse memory (r = -0.59, P = .008). There were no associations between CD4 reservoir and cognition.

Conclusions: The number of intact HIV genomes per million monocytes was related to poorer cognition and the percentage of intermediate monocytes. These findings suggest that the presence of HIV genomes in general do not relate to cognitive complications, but intact, and therefore potentially replication-competent HIV, may contribute to cognitive complications in vsWWH.

Keywords: HIV; cognition; monocytes; reservoir; women with HIV.

Figure 1.

Higher percentages of intermediate monocytes were associated with poorer global and domain-specific cognition. Cell phenotyping data were acquired by flow cytometry on whole blood from 62 virally suppressed women with HIV. Percent CD4 T cells and monocyte MNC, and monocyte subsets were associated with cognition. **P < .01, *P < .05, ^†P > .05 and P < .10. Abbreviations: AWM, attention working memory; EF, executive function; M, mean; MNC, mononuclear cells; SD, standard deviation.

Figure 2.

Intact proviral DNA was detected in monocytes from a subset of vsWWH. Monocytes (A) and CD4 T cells (B) were isolated from 53 vsWWH and assessed for HIV proviral DNA using intact proviral DNA assays, line indicates median. C, 3′ defective (del/HM), 5′ defective (del/HM), intact, and total proviral genome levels per million cells were compared in participants who had measurable DNA levels in both cell types: 3′ del/HM n = 44, *P = .02; 5′ del/HM n = 38, ***P = .0002; intact n = 20, ns P = .09; total n = 49, ***P = .001, paired t test. Abbreviation: del, deleted; HM, hypermutated; LOD, limit of detection; ns, not significant; vsWWH, virally suppressed women with HIV.

Figure 3.

Number of intact HIV genomes in monocytes from vsWWH associated with poorer cognition. A, Detectable IPDA signal in monocytes and CD4 T cells from vsWWH were associated with concurrent cognitive outcomes and r values are displayed as a heatmap. Negative associations are shown in red and positive associations in blue; sample number differed for each IPDA measure as each subject had a unique make up of HIV genomes, as shown in the figure under each genome category. *P < .05, ^‡P = .05, ^†P > .05 and P < .10. B, Significant associations with intact genomes per million monocytes and each cognitive domain, n = 20, r and P values are displayed in each graph; simple linear regression. C, The data set was split into categorical variables, no intact (n = 33) and yes intact (n = 20), to compare cognitive z scores for each category, line indicates median. Abbreviations: AWM, attention working memory; del, deleted; EF, executive function; IPDA, intact proviral DNA assay; M, mean; SD, standard deviation; vsWWH, virally suppressed women with HIV.

Figure 4.

Amount of intact HIV genomes in monocytes were associated with the percent of intermediate monocytes in blood. A, Percentage of mononuclear cell (MNC) TLR2⁺, classical, intermediate, and nonclassical monocytes in blood were associated with intact copies per million monocytes, n = 19 (1 subject was missing flow cytometry data); negative associations are shown in red and positive associations in blue. **P < .01. B, Significant associations between intact genomes per million monocytes and intermediate monocyte percentages; r and P values are displayed; simple linear regression. C, Data were split into 2 groups: intact (n = 19) and not intact (n = 33), to compare group differences in intermediate monocyte percentages, line indicates median.

Figure 5.

Ratio of intact genomes to intermediate monocytes associated with verbal memory in virally suppressed women with HIV. A, Ratio of total HIV genomes and intact genomes per intermediate monocytes were associated with global cognition, global SD, verbal memory, verbal recognition, and fine motor. Negative associations are shown in red and positive associations in blue, n = 19. **P < .01, ^†P > .05 and P < .10. B, Significant and trending associations between the ratio of intact genomes per million intermediate monocytes and cognitive domains, n = 19; r and P values are displayed in each graph; simple linear regression. Abbreviations: M, mean; SD, standard deviation.