Effects of Targeting Immune Activation and Intestinal Barrier on Comorbidities in People with HIV

Project Summary/Abstract People living with HIV infection have increased risk of comorbidities including cardiovascular disease, obesity and diabetes mellitus, despite effective antiretroviral therapy. Emerging evidence show that residual persistent immune dysregulation contributes to comorbidities in the HIV population. Cardiovascular disease and metabolic disorders are important comorbidities affecting people aging with HIV. The NIH K24 Midcareer Investigator Award in Patient-Oriented Research would provide crucial support to enable advancement of my patient-oriented research into mechanisms and potential prevention and treatment strategies for atherosclerosis and metabolic diseases including obesity, abnormal adipose tissue, insulin resistance and diabetes mellitus in people with HIV. I currently lead multidisciplinary teams and our interdisciplinary studies with rich collaborations with HIV virologists, immunologists, infectious disease clinical trialists, cardiologists, gastroenterologists, pathologists, and biostatisticians provide an exciting research platform for mentoring. Importantly, the support of the K24 Award would allow me to have dedicated and protected time to mentor new physician scientists in clinical investigation. This award would also allow me to develop my own skills in mentoring, leadership and research, and to advance scientific research on comorbidities in people with HIV, especially metabolic and cardiovascular comorbidities related to chronic immune inactivation in people living with chronic HIV. Mentoring training will be provided utilizing my NIH funded studies to provide trainees with opportunities to 1) investigate gastrointestinal mucosal barrier in people with HIV and its role in chronic inflammation, immune activation and cardiovascular disease risk using existing data and intestinal biopsy samples already collected and 2) to prospectively investigate the effects of CCR2 and CCR5 chemokine receptor antagonism on immune activation, cardiovascular disease risk and metabolism in a multicenter placebo-controlled, double-blind, 24-week long, randomized trial of cenicriviroc vs. placebo in adult men and women living with HIV with suppressed HIV-1 RNA on stable ART who have increased CVD risk. This study will leverage the clinical trial infrastructure of the ACTG and the extensive scientific expertise of collaborating investigators and laboratories within the ACTG and provide rich training experiences for my mentees in patient oriented clinical trial research.