Basic Science Award

Mucosal Natural Killer T (NKT) cells and the Gut Microbiome in HIV-1 Infection

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Invariant natural killer T (NKT) cells are innate-like T cells that respond to lipid antigens presented on the MHC class I-like molecule CD1d. These immunoregulatory cells have the capacity for abundant cytokine release almost immediately after antigen recognition and are essential for the activation of multiple arms of the immune response, including dendritic cells, conventional T cells and B cells. Murine studies have shown that the intestinal microbiome is an important factor in the maturation of functional NKT cells. NKT cells are depleted in the peripheral blood of HIV-1-infected subjects. However, their role in the gastrointestinal-associated lymphoid tissue (GALT) in these individuals is unknown. Our preliminary data suggest that human NKT cells are found at a higher frequency in GALT compared to blood, particularly in individuals who control HIV-1 replication in the absence of treatment. Prior studies examining the effect of antiretroviral therapy (ART) on the recovery of NKT cells in HIV-1 infection have been conflicting and have not included analyses of this subset in the mucosal compartment. Bacteroides fragilis has recently been reported to produce a sphingolipid that potently stimulates NKT cells, and this species is depleted in the gastrointestinal tract of subjects with untreated HIV-1 infection. We therefore hypothesize that individuals who initiate ART early in the course of infection will have preservation of this and other commensal organisms, coupled with preferential recovery of mucosal NKT cells. To test this hypothesis, we propose a one-year pilot study in which we will measure NKT frequency and function in peripheral blood and GALT in parallel with characterization of the intestinal microbiome. We will compare these measures in a cross-sectional cohort of HIV-1-infected individuals who have initiated ART early, subjects who began ART later, ART-nave individuals, and uninfected controls.