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

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.