Latent HIV Infection of BBB Pericytes Enhances Gap Junction-mediated Crosstalk with Endothelial Cells.

Abstract

HIV-Associated Neurocognitive Impairments persist, with over 50% of patients experiencing cognitive decline. Blood-brain barrier (BBB) impairment is a consistent feature of this comorbidity, which is remarkable, because BBB endothelial cells are not productively infected by HIV-1. Conversely, pericytes can be productively infected with HIV-1 and are essential for cerebrovascular homeostasis. Given this, we hypothesized that HIV-1 infection of pericytes disrupts BBB endothelial cell integrity through dysfunctional gap junction and hemichannel signaling, impairing pericyte-endothelial intercellular communication. Using a co-culture model with primary human BBB pericytes and brain microvascular endothelial cells, pericytes were infected with HIV-1 for 3 or 7 days, exhibiting active and latent viral phenotypes. Findings revealed enhanced gap junction communication between HIV-infected pericytes and endothelial cells under both conditions, and blocking gap junctions modulated endothelial inflammatory responses. Overall, this study advances our understanding of the molecular mechanisms underlying HIV-associated BBB dysfunction and may inform the development of targeted therapeutic strategies.