HIV heart inflammation is mediated by HIV infected myeloid cells, HIV-tat secretion, and aberrant function of Connexin43-containing channels

People living with HIV (PLWH) have a 2 times higher risk of HIV-associated cardiovascular disease (HIV-CVD) compared to people without HIV, despite effective anti-retroviral therapy (ART), but the mechanism is unknown. Here, we demonstrated the presence of myeloid cells containing HIV DNA sequences (HIV⁺) in human ventricular heart tissues from people with HIV in the ART era. HIV⁺ cells show residual HIV-Tat expression that is associated with upregulation of Connexin43 (Cx43) expression, gap junctional communication, and hemichannel (HC) activity. HIV-Tat binds to the Cx43 promoter, increasing Cx43 mRNA and protein expression. Cx43 enhanced expression by HIV-Tat was localized in the intercalated disk, as well as in the lateral membrane of cardiomyocytes, resulting in Cx43-containing HC openings and release of PGE₂ and ATP, as well as facilitating the secretion of inflammatory cytokines. Overall, our data demonstrated that HIV⁺ cells, even during ART, secrete HIV-Tat, compromising GJ and HC-mediated communication and promoting localized inflammation, which could contribute to arrhythmia.