Role of HIV gp120 and Nef in Transcriptome Dysregulation and Pulmonary Vascular Remodeling

PROJECT SUMMARY People living with HIV (PLWH) are at a significantly high risk of developing Pulmonary Hypertension (PH), which can lead to death by heart failure, even with the suppressive effects of antiretroviral therapy (ART). PH is characterized by phenotypic changes in endothelial cells that result in increased pulmonary artery pressures and right ventricular hypertrophy. However, the underlying mechanism of how HIV contributes to the development of HIV-PH is still not fully understood. Our team has previously identified an association between specific HIV polymorphisms and the susceptibility to HIV-PH in patients. This proposal focuses on increasing the knowledge of how the pulmonary vasculature responds to HIV and determining how specific HIV polymorphisms contribute to the pathogenesis of HIV-associated vascular disease. To address this gap in knowledge, and guided by the literature and our preliminary studies, we propose conducting experiments in human vascular cells in vitro and in hu-mice to investigate the role of the CXCR4 signaling pathway elicited by HIV-PH polymorphisms in ECs, the impact of HIV-PH variants and ART in SMC constriction in vitro and in pulmonary vascular hemodynamics in hu- mice and transcriptomics (using scRNA-seq) and epigenomics (using scATAC-seq) changes induced by HIV- PH in pulmonary vascular cell sub-populations in hu-mice. This proposal addresses high-priority research areas established by the Office of AIDS Research and the NHLBI by addressing PH as an HIV-associated comorbidity that is not improved by ART. Our findings will inform future therapeutic advances tailored to HIV-PH. The strengths of this proposal build upon its multifaceted approach, compelling data on the role of HIV proteins in PH, access to HIV-PH biospecimens, utilization of a novel mouse model of HIV-PH, and a strong team of investigators with significant and complementary expertise.