Host Genetic Predictors of IDO-induced Tryptophan Catabolism Among HIV Infected Ugandans Maintaining Treatment-Mediated Viral Suppression

Millions of HIV-infected Africans now receive life-saving antiretroviral therapy (ART). However, mortality remains high, and persistent immune activation during early ART-mediated viral suppression is an independent predictor of mortality in this setting. Studies have shown that generalized immune activation accelerates clinical progression of untreated HIV disease, persists during therapy, predicts poor immune recovery during suppressive ART, and may lead to increased mortality. One potential inflammatory pathway mediating morbidity and mortality is the tryptophan oxidative (TOx) pathway. In the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort, we found that the extent of tryptophan catabolism is a major predictor of both CD4+ T cell recovery and mortality among HIV-infected Ugandans initiating ART. In the current proposal, we will assess the host genetic determinants of the TOx pathway in this setting to identify targets for novel interventions. Specifically, we will use a candidate gene approach focusing on genes known to interact with the TOx pathway (Aim 1) and a discovery-based GWAS approach (Aim 2) to identify the most important host genetic determinants of the TOx pathway in vivo. This work leverages existing data and samples from the UARTO and Anti- Retroviral for Kaposi's Sarcoma ARKS cohorts, benefits from a multidisciplinary mentoring team of Drs. Hunt (Immunology), Kroetz (Genetics), and Witte (Bioinformatics), and will help develop important preliminary data for a future K23 proposal.