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Principal Investigator: SHEILA COLLINS
Organization: VANDERBILT UNIVERSITY MEDICAL CENTER
Fiscal Year: 2024
Award: $808,810
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
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.
Terms: <AIDS Virus><Academic Medical Centers><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Adipocytes><Adipose Cell><Adipose tissue><Adult-Onset Diabetes Mellitus><Age><Architecture><Aspiration Lipectomy><Aspiration Lipolysis><Automobile Driving><Body Regions><Body Tissues><Body Weight><Body fat><CAT scan><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CT X Ray><CT Xray><CT imaging><CT scan><Caloric Intake><Cardiometabolic Disease><Cardiometabolic Disorder><Cell Body><Cell Function><Cell Physiology><Cell Process><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cholesterol><Clinical><Clinical Research><Clinical Study><Computed Tomography><Data><Defect><Deposit><Deposition><Development><Diabetes Mellitus><Dysfunction><Energy Expenditure><Energy Intake><Energy Metabolism><Engineering / Architecture><Environment><Fat Cells><Fats><Fatty Tissue><Fatty acid glycerol esters><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Functional disorder><Future><Gene Expression><General Population><General Public><Genes><Goals><HIV><HIV Infections><HIV Seronegativities><HIV Seronegativity><HIV negative><HTLV-III Infections><HTLV-III Seronegativities><HTLV-III Seronegativity><HTLV-III-LAV Infections><Human><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Image><Immune><Immune Cell Activation><Immunes><Immunology><Impairment><Indirect Calorimetry><Inflammation><Inflammatory><Insulin Resistance><Integrase><Intermediary Metabolism><Intervention Studies><Intra-abdominal><Ketosis-Resistant Diabetes Mellitus><LAV-HTLV-III><Link><Lipid Trafficking><Lipids><Lipocytes><Liposuction><Liver><Longitudinal Studies><Lymphadenopathy-Associated Virus><Mature Lipocyte><Mature fat cell><Maturity-Onset Diabetes Mellitus><Measurement><Mediating><Metabolic><Metabolic Diseases><Metabolic Disorder><Metabolic Processes><Metabolism><Modeling><Modern Man><Modernization><NIDDM><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Obesity><Organ><Pathway interactions><Persons><Pharmaceutical Agent><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Physiology><Physiopathology><Procedures><Radiography><Regimen><Respiration Calorimetry><Risk><Risk Reduction><Roentgenography><Role><Science><Skeletal Muscle><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><Subcellular Process><Suction Lipectomy><Suction Lipolysis><T-Cell Subsets><T-Cells><T-Lymphocyte><T-Lymphocyte Subsets><T2 DM><T2D><T2DM><T4 Cells><T4 Lymphocytes><Technology><Testing><Thesaurismosis><Tissues><Tomodensitometry><Transferase><Transferase Gene><Triacylglycerol><Triglycerides><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><University Medical Centers><Viral><Virus-HIV><Visceral><Voluntary Muscle><Weight><Weight Gain><Weight Increase><X-Ray CAT Scan><X-Ray Computed Tomography><X-Ray Computerized Tomography><Xray CAT scan><Xray Computed Tomography><Xray computerized tomography><adipocyte biology><adipose><adiposity><adult onset diabetes><ages><antiretroviral therapy><antiretroviral treatment><body weight gain><body weight increase><caloric dietary content><cardiometabolic><cardiometabolism><catscan><co-morbid><co-morbidity><comorbidity><computed axial tomography><computer tomography><computerized axial tomography><computerized tomography><corpulence><cytotoxic><density><developmental><diabetes><doubly-labeled water><driving><energy balance><fatty acid oxidation><flow cytophotometry><hepatic body system><hepatic organ system><high risk><imaging><immune activation><inhibitor><insulin resistant><insulin tolerance><intervention research><interventional research><interventional study><interventions research><ketosis resistant diabetes><lipid transport><long-term study><longitudinal outcome studies><longterm study><maturity onset diabetes><metabolism disorder><multidisciplinary><non-contrast CT><noncontrast CT><noncontrast computed tomography><nutrition><pathophysiology><pathway><pharmaceutical><prevent><preventing><radiologic imaging><radiological imaging><reduce risk><reduce risks><reduce that risk><reduce the risk><reduce these risks><reduces risk><reduces the risk><reducing risk><reducing the risk><risk-reducing><social role><subcutaneous><subdermal><thymus derived lymphocyte><transcriptomics><type 2 DM><type II DM><type two diabetes><weights><white adipose tissue><wt gain><yellow adipose tissue>