Determining the interplay of MAIT cells and the translocated microbiome in HIV-induced neuroinflammation

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Summary/Abstract Significant progress in the treatment of HIV with suppressive ART has led to long term viral suppression; however, people living with HIV (PLWH) continue to experience CNS perturbations including HIV-associated neurocognitive disorders (HAND). Persistent CNS immune activation is a hallmark of HIV neuropathogenesis, and persists even in PLWH who are on suppressive ART. The identification of persistent intestinal dysbiosis in people living with HIV (PLWH) and ongoing neurological disorders despite ART has highlighted the importance of gut–brain communication in the pathogenesis of central nervous system (CNS) co-morbidities in PLWH. However, the question regarding the identity of immunological, microbial, and central nervous system components responsible for this crosstalk remains unclear. Our studies of mucosal-associated invariant T cells (MAIT cells), which are innate-like T cells able to recognize conserved bacterial ligands presented by MHC- related 1 (MR1) molecule, during HIV-1 infection have shown that MAIT cells are activated early during infection and expand in blood and colonic mucosa coincident with peak viremia, in a manner associated with emerging microbial translocation. Moreover, preliminary single cell transcriptomic and TCR sequencing data from our group has detected a large proportion of MAIT cells in cerebrospinal fluid (CSF) of PLWH, suggesting MAIT cells may serve as immune mediator of the gut-brain axis. Yet, a MAIT cell immune mediated gut-brain axis mechanism has not been studied in HIV infection. We hypothesize that MAIT cells are a major immune cell type that mediate the crosstalk between gut dysbiosis, microbial translocation, immune cell dysfunction, and CNS co- morbidities in PLWH. To comprehensively study MAIT cells across compartments including the CNS, we will leverage already collected biospecimens of gut, cryopreserved peripheral blood mononuclear cells, plasma, CSF fluid, cryopreserved CSF cell pellets, and postmortem brain tissues samples from a previous non-human primate study conducted by MHRP using SHIV-1157ipd3N4. In Aim 1, we will longitudinally compare and contrast the relationship between the gut microbiome to the MAIT cells residing in CSF, blood, gut, and brain during SHIV infection, post ART, and following analytical treatment interruption. In aim 2, we will determine the effects of translocated microbiome upon MAIT-neural cell interactions. Overall, the findings from this R21 proposal could open new immunotherapy avenues for PLWH with neurological disorders despite virological suppression by ART by targeting MAIT cells as one of the key immune mediators of the gut-brain axis.