SIV/HIV Induces Arachidonic Acid-Mediated Inflammation in the Heart by a Pannexin-1 Mechanism

HIV-associated cardiovascular disease (HIV-CVD) is a major comorbidity in people living with HIV, despite effective antiretroviral therapy (ART). The mechanisms of HIV-CVD have been associated with inflammation, ART toxicity, residual viral replication, and the presence of viral reservoirs, but the data suggest that Pannexin-1 (Panx-1) channels also play a role in HIV residual inflammation, but its contribution to HIV-CVD is unknown. Here, left ventricular heart tissues from acutely SIV-infected nonhuman primates and from chronically HIV-infected humans on suppressive ART were analyzed by mass spectroscopy imaging, showing a significant increase in the levels of arachidonic acid (AA) esterified to phospholipids and the critical enzymes involved in its metabolism, cyclooxygenase-2 (COX-2) and leukotriene A4 hydrolase (LTA4H). Most of the heart AA-associated inflammation induced by the virus was associated with infiltrated macrophages and the main source of AA. Systemic treatment of SIV-infected macaques with the Panx-1 blocker, ¹⁰Panx peptide, prevented monocyte/macrophage infiltration into the tissues, expression of COX-2/LTA4H, and AA-related inflammation. A similar profile of inflammation and increased expression of LTA4H and COX-2 enzymes was also observed in post-mortem human heart tissues from people living with HIV, suggesting that AA inflammation is present during acute and chronic infection. In conclusion, blocking Panx-1 channels after infection may offer a novel therapeutic approach to prevent or ameliorate HIV-CVD.