PROJECT SUMMARY/ ABSTRACT Around one third of transgender individuals in the United States are living with HIV. People with HIV on anti- retroviral therapy face an increased risk of cardiometabolic disease, even after controlling for traditional risk factors. Gender-affirming hormone therapy, in turn, may adversely affect the metabolic health of transgender women by increasing visceral adipose tissue and may also increase the risk of myocardial infarctions and venous thromboembolism. The increased risk for cardiometabolic disease among PWH together with the known effects of gender-affirming hormone therapy among non-HIV-infected transgender women underscores the significance of the aims of this proposal. The central hypothesis for this proposal is that gender-affirming hormone therapy in transgender WHIV will have both beneficial and adverse cardiometabolic effects, reflecting complex downstream consequences of concomitant testosterone suppression and estrogen replacement. The candidate will apply a highly innovative approach to, for the first time, prospectively investigate the effect of testosterone suppression and estrogen therapy on: aim 1 - body composition, ectopic fat deposition, insulin sensitivity, and lipid levels, aim 2 – myocardial structure and function; aim 3 – coagulation parameters (including coagulation factors and tissue factor expression on monocytes). This proposal will provide critically needed information regarding the safety of gender-affirming therapy in this population and identify possible targets for adjunctive therapies to hormone therapy which may optimize the cardiometabolic health of transgender WHIV. The candidate is an outstanding clinical investigator who is dedicated to developing her own research track centered on the cardiometabolic health of transgender individuals living with HIV. In the short term, she hopes to obtain the necessary skills to independently pursue patient-oriented physiology research in the field of transgender medicine in HIV and the preliminary data for an RO1 proposal. In the long term, she plans to utilize these skills and preliminary data to become an R01-funded clinical investigator. This proposal will be supported by an excellent team of mentors and collaborators who will provide complementary expertise in the areas of HIV-associated cardiometabolic disease, Cardiology, Infectious Disease, Immunology and Biostatistics. The institutional environment of Massachusetts General Hospital (MGH) and Harvard-affiliated institutions will provide the candidate excellent resources and opportunities for successful completion of the proposed study and her career development plan. .