Impact of Microbial Dysbiosis on MAIT Cell Tissue Repair Program after Acute HIV Infection

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Project Summary / Abstract Mucosa-associated invariant T-cells (MAIT) are a subset of unconventional, innate-like T cells that are highly abundant in mucosal tissues and peripheral blood and recognize microbial vitamin B2 (riboflavin) metabolites from a wide range of microbes. Furthermore, MAIT cells have been recently shown to have tissue repair functions. In HIV infection, MAIT cells are irreversibly lost in the blood and gut, and remaining cells display elevated signs of activation with decreased functional potential. Another consequence of HIV is a profound dysbiosis of the gut microbiome characterized by reshaped abundances of commensals turned pathogenic. HIV- associated compromised gut mucosal immunity is thought to be a major driver of persistent immune activation, viral replication, and morbidity and mortality, even in individuals who are on effective ART. Studies show that chronic HIV infection is associated with reduced gut bacterial diversity and an enrichment in fusobacteria, associated with reduced T cell counts and higher inflammation. Yet, the etiology of dysbiosis in HIV infection remains unclear. We have an unprecedented opportunity to address this significant gap in knowledge by leveraging matched biospecimens of gut tissue biopsies and peripheral blood mononuclear cells (PBMCs) from treatment naïve and ART-treated acutely and chronically HIV infected individuals enrolled in an observational HIV study in Thailand. Because of associations with gut integrity and control of microbial infections, the dysfunction of MAIT cells in HIV-1 infection may leave the host with weakened mucosal and antimicrobial immunity. To date, no studies have linked MAIT cells with surrogates of gut integrity, microbial translocation, or specific makeup of the microbiota in gut tissue during HIV infection. The overall goals of the project are to: (a) determine if imbalance in the normal gut microbiota impacts MAIT cell frequency, phenotype, and tissue repair function across stages of HIV infection; and (b) to ascertain if ART initiated early in acute HIV infection alters the relationship between the initial perturbations of the gut microbiota and the early engagement of the MAIT cell compartment. In AIM 1, we will perform MAIT cell and microbiome analysis on matched PBMCs and plasma samples from treatment naïve acutely HIV infected individuals, and HIV uninfected healthy controls matched for age and gender. We will examine if increases in translocated fusobacteria are associated with change in MAIT cells numbers and activation in the blood and gut. We will investigate if HIV-induced dysfunction of MAIT cells is associated with markers of reduced gut barrier integrity. In AIM 2, we will use PBMCs and plasma samples from uninfected and HIV-infected individuals that initiated treatment at different stages of acute infection to evaluate the impact of ART initiation timing on microbial dysbiosis and MAIT cell tissue repair functions. In vitro experiments will be performed to study the impact of fusobacteria on MAIT cell dysfunction. By investigating these two aims we will determine if commensal and pathogenic gut microbiota tune the number, phenotype, and functions of peripheral and gut MAIT cells in HIV infection.