Project Summary Improved survival among human immuno-deficiency virus (HIV-1) infected individuals with the advent of antiretroviral therapy has clearly led to serious increase in the prevalence of noninfectious complications. In this regard, one of the most devastating sequelae is the development of pulmonary arterial hypertension in HIV-infected individuals (HPAH). Intravenous drug use (IVDU) accounts for one-third of all new cases of AIDS in the United States and has been identified as the most common risk factor in the individuals diagnosed with HPAH. Our recent findings showing enhanced pulmonary vascular remodeling in HIV-infected lung tissues from IV heroin and/or cocaine abusers and in -infected macaques exposed to morphine indicate that illicit drugs and HIV-1 potentially act in concert to cause pulmonary arteriopathy. Furthermore, SIV-infected morphine treated macaques were found to have increased number of apoptotic endothelial cells in the early stage lesions, whereas complete occlusion by actively proliferating endothelial simian immunodeficiency (SIV) cells was observed in the advanced stage plexiform lesions. This observation was further supported by our in- vitro findings showing enhanced apoptosis followed by significantly increased proliferation of human pulmonary endothelial cells on simultaneous treatment with HIV- transactivator of transcription (Tat) protein and morphine compared to either treatment alone. Based on our recent findings, the hypothesis of our study is that the combined exposure of pulmonary endothelial cells to HIV-protein(s) and morphine results in the induction of autophagy that leads to enhanced proliferation of endothelial cells and severe pulmonary vascular remodeling. This hypothesis will be tested by pursuing three specific aims. In the first aim we will evaluate the effect of HIV- Tat and morphine on the oxidative stress mediated regulation of bulk autophagy in endothelial cells. In the second aim, we propose to delineate the role of autophagy/mitophagy in Tat and morphine mediated enhanced proliferation. Third aim will be focused on in-vivo investigation of PAH and autophagy in HIV-1 Tg rats with or without morphine exposure. These studies are innovative because to the best of our knowledge it will be the first attempt to understand the potential link between the role of autophagy/mitophagy in the morphine and HIV-proteins mediated apoptosis resistant enhanced proliferation. The proposed research will enhance our understanding of the fundamental mechanisms involved in the pathogenesis of HPAH and therefore is directly responsive to RFA-HL-14-024 (Basic Research in the Pathogenesis of HIV-Related Heart, Lung, and Blood (HLB) Diseases in Adults and Children).

Project Narrative The proposed research will have an important positive impact on human health because understanding the basis of pathogenesis and identification of mechanism(s) and the molecules involved in the development of HIV associated PAH are expected to provide new targets for therapeutic interventions that will aid the growing number of HIV-infected and/or intravenous drug users. In addition, the results will fundamentally advance the field of cardio-pulmonary vascular research in general.