Abstract: More than 25% of middle-aged people living with HIV-1 infection (PLWH) have early onset myocardial diseases including diastolic dysfunction (DD), harbingers for symptomatic heart failure, dyspnea, pulmonary abnormalities, frequent hospitalizations, and sudden cardiac death.8-16 To date, the molecular causes for the myocardial dysfunction in PLWH remain poorly understood. This paucity of information and a lack of treatment options have prompted the OAR to list “Strategies to Prevent and Treat HIV-Associated Heart Diseases” as areas of high priority for HIV research. We hypothesize that “early onset myocardial dysfunction in PLWH is arising from accumulation of cytotoxic glycolysis metabolite, methylglyoxal (MG) as a result of persistent cardiac inflammation.” This hypothesis is based on several lines of new evidence recently obtained in our laboratories. First, HIV-1 infected humanized NOD/Scid-IL2Rg-/-(NSG) mice reconstituted with human immune system (Hu-NSG) develop a progressive cardiomyopathy akin to that seen in patients. Second, cART lowers plasma HIV-1 viremia but does not lower cardiac inflammation indicated by upregulation of the inflammation-biomarker, vascular adhesion protein-1 (VAP-1). Third, the cytotoxic glycolysis by-product MG, accumulated in hearts of HIV-1 infected Hu-NSG mice with/without cART due to inflammation-induced downregulation of MG-degrading enzyme glyoxalase-1 (Glo1). Elevated MG form MG-H1 adduct on proteins. Fourth, increased VAP-1 and MG-H1, and reduced Glo1 were found in autopsied ventricular tissues from HIV-1 patients, indicating clinical relevance of our findings. Fifth, administration of an engineered adeno-associated virus that uses the promoter of an inflammation-induced protein, endothelin-1 (AAV2/9-Endo-Glo1) to express Glo1 in hearts of Hu-NSG mice, attenuate coronary microvascular leakage, ischemia, fibrosis and myocardial dysfunction, establishing a cause-effect relationship between MG accumulation and myocardial dysfunction. This multi-PI project brings together the expertise of Drs. Keshore R. Bidasee (M-PI, heart failure) and Santhi Gorantla (M-PI, humanized mice and HIV-1 infection) and build on these findings to (1) delineate the pathobiological trajectories responsible for HIV-1 associated cardiac dysfunction in Hu-NSG mice in the absence and presence of cART; (2) delineate molecular mechanisms responsible for elevation of cardiac inflammation in cART-treated HIV-infected Hu-NSG mice and validate the findings in autopsied tissues from HIV-1 infected patients, and (3) investigate whether attenuating MG accumulation in HIV-infected and cART-treated Hu-NSG mice will blunt myocardial dysfunction. Accomplishments of these aims will not only define for the first time a novel link between inflammation and myocardial dysfunction in the setting of HIV-1 infection, but the data could pave the way for the development of urgently needed therapeutics to mitigate early onset myocardial dysfunction i...