MAGIC-PHIV: Microbiome and Gut Inflammation in Cardiometabolic Health in Youth with Perinatally Acquired HIV - Project Summary/Abstract There are 2.1 million children under 15 years living with HIV worldwide; the vast majority have perinatally acquired HIV (YPHIV) and reside in Eastern and Southern Africa. YPHIV are now expected to live through adolescence and well into adulthood, such that adolescents now represent the largest growing population living with HIV. Several comorbidities, including cardiometabolic, have been associated with heightened immune activation and inflammation despite viral suppression in adults living with HIV. The mechanisms causing HIV-associated immune activation, remain incompletely understood, but alteration of the interplay between gut mucosa and the compositional and functional shifts in microbiota appear to play a central factor. Despite significant advances in our understanding of how HIV disrupts intestinal integrity, key limitations in existing studies include (1) the underlying molecular mechanisms of many microbiome associations remain unstudied, such as bacterial functional dynamics or immune modulation, (2) the lack of an appropriate control group to address potential environmental confounders, and (3) the lack of investigations in YPHIV specifically in sub-Saharan Africa where the vast majority of YPHIV reside. The overall goal of this project is to obtain new insight into gut dysbiosis in YPHIV and to identify unique microbiome-related inflammatory signaling cascades related to metabolic disturbances. We will use a multi-omics approach to identify alterations in the gut microbiome, at a strain and functional level in YPHIV and identify microbiome and metabolite pathways related to immune activation and metabolic disturbances. We will address our hypothesis through three aims: 1) we will characterize and compare the gut microbiome in YPHIV and an uninfected comparison group using metagenomics and metabolomics; 2) we will correlate our existing data on immune activation and inflammation to the microbiome data generated; and 3) we will identify unique microbiome-related inflammatory signaling cascades to metabolic health (insulin resistance, adiposity and dyslipidemia). This study will build on the existing and well-phenotyped cohort of virally suppressed YPHIV and age-and sex- matched uninfected comparison group in urban and rural Uganda and utilize repository specimens. The 2 cohorts in urban and rural settings will allow for data validation and replication, a major criticism of prior observational omics studies. This will serve as preliminary data for future grant applications focused on the application of existing and development of novel and precision therapeutics that may have a considerable impact on both survival and quality of life in this young population by decreasing cardiometabolic complications.
