Abstract 11752: Pitavastatin Treatment Ameliorates HIV-Nef Containing Extracellular Vesicle-Mediated Cardiomyocyte Dysfunction

Rationale: The prevalence of cardiovascular diseases such as heart failure and left ventricular diastolic dysfunction remains high in People Living With HIV (PLWH) even with the advent of modern anti-retroviral therapy (ART). Sustained plasma persistence of the pro-inflammatory HIV protein Nef within extracellular vesicles (EV) of ART-treated patients may contribute to continued disease progression. We hypothesized that HIV-Nef induces cardiomyocyte dysfunction by elevating Reactive Oxygen Species (ROS) production which then increases apoptosis and senescence in cardiomyocytes. Results: Network analysis using Metacore of cytosolic and nuclear proteomics of human cardiomyocytes stimulated with HIV-Nef EV demonstrated changes in metabolic processes, DNA damage, oxidative stress and cytoskeletal remodeling. HIV-Nef EV promotes cardiomyocyte cellular dysfunction as evidenced by increased ROS production, DNA damage, apoptosis and premature senescence in both AC-16 cardiomyocyte cell line (n=5, p<0.001) and iPSC-derived cardiomyocytes (n=4, p<0.01). HIV-Nef EV stimulation induced cardiomyocyte metabolic switch by increasing consumption of anaerobic substrate (Lactic Acid) and decreasing consumption of TCA substrate (Citric Acid). [AE1] Network-science powered pathway analysis of HIV-Nef EV stimulated cardiomyocytes identified a key hub in Rac1-GTPase mediated pathways. Proteomic analysis of HIV-Nef transfected HEK293T cells indicated pitavastatin treatment altered Rac1 trafficking to inhibit interaction with HIV-Nef, suggesting a potential protective mechanism. Subsequently, cardiomyocyte dysfunction was abrogated by clinically relevant doses of pitavastatin (10-100nM ,n=4, p<0.01). Addition of HIV-Nef EV supernatant to AC-16 cardiomyocytes but not to those treated with pitavastatin increased chemotaxis of primary human macrophages (n=4, p<0.05). Conclusion: Pitavastatin treatment may prevent Nef EV-mediated cardiac dysfunction and inflammation in HIV patients. [AE1]I suggest including numbers of technical or biological replicates and p values when possible.