Abstract 14459: Endothelial Cell Specific Expression of HIV-Nef Induces Endothelial Senescence and Reduced Cardiac Output

Abstract

Introduction: People living with HIV experience increased cardiovascular comorbidities despite immediate prescription of combined antiviral therapy (ART) upon HIV diagnosis. Previously, we reported that the virally encoded HIV-Nef protein persists in extracellular vesicles (EV) of aviremic HIV patients on ART and endothelial-specific transgenic expression of HIV-Nef in murine models causes increased endothelial surface expression of the pro-apoptotic protein EMAPII. Co-culture with HIV-Nef expressing T cells induced endothelial senescence which could be completely abrogated by using EMAPII-neutralizing antibodies. Hypothesis: Here we hypothesize that endothelial Nef expression in transgenic mice induces EMAPII-associated endothelial senescence after intermittent exposure to hypoxia. Methods: Female (n=5) transgenic mice with endothelium-specific Nef expression using VE-Cadherin promoter were challenged with 4 weeks of mild hypoxia (10% O 2 ) followed by 8 weeks of normoxia and then evaluated for cardiac function using non-invasive echocardiography with INVEVO2100. Results: We observed decreased cardiac output (Nef= 15.10 ul/min vs WT= 21.46 ul/min, p<0.05). Subsequently, we observed a 3.5-fold increased frequency of senescent endothelial cells using the senescence-associated marker p16INK4α (Nef= 0.54% vs WT= 0.15%, p<0.05) from the heart using flow cytometry. Furthermore, we also observed a 3.5-fold increase in the frequency of EMAPII+/P16INK4α+ cells (Nef= 0.50% vs WT= 0.14%, p<0.05). Conclusions: Transgenic endothelial HIV-Nef expression leads to upregulation of endothelial cellular senescence and EMAPII expression. EMAPII-neutralizing antibodies and senolytic agents are likely tools to reduce HIV-Nef-induced senescence. Endothelial cell senescence could affect cardiac circulation to impair heart function. Future studies will evaluate sex differences in HIV-Nef induces cardiac output at various ages.