CD14+CD16+ monocyte transmigration across the blood-brain barrier is associated with HIV-NCI despite viral suppression

Abstract

HIV-associated neurocognitive impairment (HIV-NCI) affects 15%-50% of people with HIV (PWH), despite viral suppression with antiretroviral therapy (ART). HIV neuropathogenesis is mediated, in part, by transmigration of infected CD14+CD16+ monocytes across the blood-brain barrier (BBB) into the central nervous system (CNS). In the CNS, CD14+CD16+ monocytes contribute to infection and activation of parenchymal cells, resulting in production of neurotoxic viral and host factors that cause neuronal damage. Mechanisms by which CD14+CD16+ monocytes contribute to HIV-NCI have not been characterized in a study population of PWH on ART without contribution from confounders that affect cognition (e.g., substance use, hepatitis C virus coinfection). We assessed cognitive function, PBMC transmigration across the BBB, and neuronal health markers in a well-defined cohort of 56 PWH on ART using stringent criteria to eliminate confounding factors. We demonstrated that PWH on ART with HIV-NCI have significantly increased transmigration of their CD14+CD16+ monocytes across the BBB compared with those with normal cognition. We showed that hypertension and diabetes may be effect modifiers on the association between CD14+CD16+ monocyte transmigration and cognition. This study underscored the persistent role of CD14+CD16+ monocytes in HIV-NCI, even in PWH with viral suppression, suggesting them as potential targets for therapeutic interventions.

Keywords: AIDS/HIV; Cell migration/adhesion; Monocytes.

Figure 1. CD14⁺CD16⁺ monocyte transmigration across the BBB is higher for PWH on ART with HIV-NCI than for those with normal cognition.

(A) The percentage of transmigration for each leukocyte subset across the BBB was calculated based on its proportion in the total cell population added to the coculture. Data are represented as mean ± SEM. Significance was determined using ANOVA with Tukey’s multiple-comparison test; ****P < 0.0001. To compare transmigration between participants, a fold-change in transmigration to CCL2 of each leukocyte subset was set relative to transmigration to media with diluent, set to 1. Fold-changes of transmigrated CD14⁺CD16⁺ monocytes (B), CD14⁺CD16^– monocytes (C), and CD3⁺ T cells (D) were compared between PWH on ART with HIV-NCI or with normal cognition (B–D). (E) Transmigration of CD14⁺CD16⁺ monocytes was compared between participants with and without an impairment in individual cognitive domains of working memory, abstraction/executive function, and speed of information processing, regardless of overall cognitive status. n = 48; data represented as medians ± 95% CI. Significance was determined by Wilcoxon’s rank sum test; *P < 0.05.

Figure 2. Hypertension and diabetes are effect modifiers on the relationship between cognition and the transmigration of CD14⁺CD16⁺ monocytes across the BBB.

(A) Associations between fold-change in transmigration of CD14⁺CD16⁺ monocytes and cognitive T scores in the domains in PWH on ART with (n = 23) and without (n = 25) hypertension. (B) Associations between fold-change in transmigration of CD14⁺CD16⁺ monocytes and cognitive T scores in PWH on ART with (n = 14) and without (n = 34) diabetes. Statistical significance of correlation was determined using Pearson’s correlation test, significance set to P < 0.05.