Pathophysiology of Metabolically Detrimental Changes in Adipose Distribution, Adipocyte Function, and Adipose Immune Environment on Antiretroviral Therapy

Abstract Excess fat accumulation and deposition of ectopic lipid in visceral adipose tissue (VAT), the liver and skeletal muscles contribute substantially to the high risk for cardiometabolic disease in persons with HIV (PWH) on antiretroviral therapy (ART). While the potential for weight gain during the first year of ART is well-recognized,

the amount of weight is highly variable, and more importantly, it is the accumulation of excess body fat and ectopic lipid that drives cardiometabolic comorbidities and complications. We hypothesize that during the first year of integrase strand transfer inhibitor (INSTI)-based therapy there is rapid onset of a state of positive energy

balance, impaired fatty acid oxidation, and impaired ability of subcutaneous adipose tissue (SAT) to store lipids (driven in part by persistent T cell-mediated SAT inflammation), which leads to the deposition of excess lipids in VAT, the liver and skeletal muscle further inhibiting the ability of these organs and tissues to function normally.

This multi-disciplinary study will be led by three established PIs with complementary expertise in the fields of HIV clinical research, adipocyte biology and physiology, nutrition, human metabolism, and imaging. We will leverage state-of-the-science procedures and technologies including comprehensive assessment of factors driving energy

balance, adipose tissue micro-liposuction, adipose tissue single cell transcriptomics, SAT gene expression, and imaging of ectopic lipid depots during the first year of INSTI-based ART in 129 treatment-naïve PWH to meet the following specific aims: Aim 1: To determine precisely when and where excess fat accumulates, including

ectopic depots (hallmarks for insulin resistance and development of diabetes) during the first year of INSTI- based ART (when viral suppression occurs), and whether the storage of excess fat in specific regions and depots is driven by excess energy intake, reduced energy expenditure, and/or reduced fatty acid oxidation; Aim 2: To

determine the specific changes in the SAT architecture, cellular composition, and transcriptomic features that contribute to body region and depot-specific ectopic fat accumulation; Aim 3: To determine the specific changes that occur in the SAT immune environment and HIV reservoir that adversely modulate adipocyte cellular function

and lipid storage. Our longitudinal study in treatment-naïve PWH during the first year of INSTI-based ART will be the first to identify mechanisms linking changes in energy balance, fatty acid oxidation, SAT architecture and function, and the impact of the SAT immune environment on adipocyte plasticity and adipocyte regulatory and

lipid trafficking pathways involved in the accumulation of VAT and ectopic lipid in the liver and skeletal muscle. The first year of ART provides a critical opportunity to prevent increased adiposity and excessive fat deposition in the intra-abdominal, liver and skeletal muscle depots, and thus reduce the risk for cardiometabolic disease in

PWH. These data will identify targets for future clinical and pharmaceutical intervention studies to prevent or re- direct body fat and ectopic lipid gain after ART initiation to prevent and/or reduce the growing burden of cardiometabolic diseases in PWH.