Podocan‐Like Protein 1 as a Novel Contributor to HIV‐Associated Pulmonary Vascular Disease

BACKGROUND: Thanks to the advent of combination antiretroviral therapy, life expectancy has noticeably increased in people with HIV; however, they also display an elevated susceptibility to developing severe pulmonary vascular disease. Despite efforts to understand the role of HIV-encoded proteins in the pathogenesis of the disease, the underlying mechanisms remain to be elucidated. METHODS: Using 3 mouse models of HIV and in vitro cell studies, we tested the hypothesis that HIV-related proteins induce pulmonary vascular disease via Podnl1 (podocan-like protein 1)-dependent mechanisms. RESULTS: We reported that the expression of HIV proteins in Tg26 mice and bone marrow transplant from Tg26 to wild-type mice promotes the development of pulmonary vascular disease with no sex differences. RNAseq and quantitative polymerase chain reaction analysis revealed, for the first time, high expression of Podnl1 in the lungs of our HIV models. Strikingly, lung specimens from people with HIV on combination antiretroviral therapy exhibit higher Podnl1 levels compared with individuals without HIV. We also revealed that the observed cardiopulmonary alterations and expression levels of Podnl1 were more pronounced in aged intact Tg26 mice. In addition, Podnl1 overexpression resulted in increased collagen-I production and pulmonary artery smooth muscle cells proliferation. Remarkably, we found that HIV-Tat (transactivator of transcription) is the only viral protein detectable in peripheral blood mononuclear cells obtained from people with HIV on combination antiretroviral therapy, and chronic exposure of mice to HIV-Tat recapitulated the cardiopulmonary complications of intact and bone marrow transplant Tg26 mice. CONCLUSIONS: We provide the first evidence that HIV-Tat and Podnl1 are important contributing factors to pulmonary vascular disease related to HIV infection, which presents potential new therapeutic avenues for the prevention of HIV-associated cardiopulmonary complications.