The advent of combination antiretroviral therapy (cART) has successfully halted viral replication and noticeably increased life expectancy; it has unexpectedly led to a higher risk for many non-AIDS-associated cardiovascular disorders. Now, people living with HIV (PWH) have a longer lifespan; however, they also display an elevated susceptibility to developing severe pulmonary vascular disease (PVD). Despite substantial efforts to understand the role of HIV-encoded proteins, which remain in circulation despite well-controlled viremia, in the pathogenesis of the disease, the underlying molecular mechanisms remain to be elucidated. Using mouse models of HIV and in vitro cell studies, we tested the hypothesis that HIV-encoded proteins induce PVD via Podocan-like protein 1 (Podnl1)-dependent mechanisms. We found that the expression of HIV proteins in Tg26 mice and bone marrow transplant from Tg26 to wild-type mice promotes the development of PVD in male and female mice with no sex differences. RNAseq, qPCR, and WB analysis revealed, for the first time, high Podnl1 expression in the lungs of our HIV models. Strikingly, lung specimens from PWH on cART show elevated Podnl1 levels compared to HIV seronegative individuals. We also determined that the HIV-induced cardiopulmonary complications and increases in Podnl1 expression were more pronounced in aged Tg26 mice. In addition, Podnl1 overexpression resulted in elevated collagen-I production and PASMCs proliferation. Importantly, quantification of HIV viral proteins in blood vessels and peripheral blood mononuclear cells (PBMCs) from PWH on cART unveiled that HIV-Tat is the only viral protein detectable in these tissues, and human PBMCs express 100 times higher levels of Tat. Finally, chronic treatment with HIV-encoded Tat protein fully reproduced the cardiopulmonary phenotype of Tg26 mice. Our study identified a new marker of PVD, Podocan-like protein 1, and demonstrated that HIV-associated PVD is dependent on HIV-Tat protein-induced, Podnl1-mediated vascular remodeling. These observations indicate that Podnl1 may be a novel therapeutic target for intervention of PVD linked to HIV Supported by NIH NHLBI 1R01HL147639, R01HL175471 (EBdC) and 1R01HL176323 (EBdC& LK). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Kovács et al. (Fri,) studied this question.