Multiomics analysis of the microbiome and subclinical cardiovascular disease in HIV infection

PROJECT SUMMARY This K01 Career Development Award application proposes a multidisciplinary 5-year training program to provide the candidate, Dr. Zheng Wang, with the experience and resources necessary to launch a successful career as an independent investigator. The training plan, developed closely with primary mentor Dr. Qibin Qi, co-mentors Drs. Robert Burk and Jorge Kizer, and an Advisory Committee (Drs. Rob Knight, Robert Kaplan, Tao Wang, and Anjali Sharma), will expand Dr. Wang’s research experience and expertise, in oral microbiome, integrative multi-omics analyses, and cardiovascular disease (CVD) epidemiology. Building upon two well- characterized HIV cohorts (Women's Interagency HIV Study, WIHS; Multicenter AIDS Cohort Study, MACS) and pre-existing circulating metabolomics and proteomics data, the proposed research project offers the candidate an exceptional opportunity to become proficient in the novel area of oral microbiome and integrative multi-omics analyses research, in the field of CVD epidemiology in HIV population. Taking advantage of collected oral saliva samples, carotid atherosclerosis (measured by ultrasound) and cardiac fibro-inflammation (measured by magnetic resonance imaging) data, circulating metabolomics data and proteomic inflammatory markers data in the WIHS, this project proposes to measure oral microbiome taxa and functional components using shotgun metagenome sequencing, in 320 participants (216 HIV+ and 104 HIV-; 84 with carotid artery plaque and 236 without plaque). We will identify alterations in the oral microbiome associated with HIV-related factors, and examine associations of oral microbiome features with subclinical carotid atherosclerosis and cardiac fibro-inflammation. We will further investigate the oral-gut microbiome crosstalk (with pre-existing gut metagenomics data) and its implications in subclinical CVD, in the context of HIV. Replication analysis will be performed in 400 MACS participants to validate the findings. Moreover, we will examine prospective associations of baseline microbial-associated metabolites with incident carotid artery plaque over 7-years follow-up (n=737), to explore the role of microbiota in CVD development. Employing advanced "multi-omics" analytical approaches, we will examine the microbiome–metabolome–proteome interactions and generate a network illustrating interrelationships between oral and gut bacteria, circulating metabolites, proteomic inflammatory markers, microbial translocation biomarkers, CVD and HIV infection. Findings from this study will provide preliminary data for a larger study proposal to measure oral and gut microbiome longitudinally and integrate microbiome with other omics data more comprehensively. These studies will advance our understanding of interrelationships among microbiome, host inflammation and metabolism, and shed light on potential underlying mechanisms, which will provide useful information for effective strategies in the prevention and management of CVD in people living with HIV.