Understanding How GI tract Damage During HIV/SIV Infection Leads to Enteric Nervous System (ENS) Dysfunction and CNS Neuroinflammation - PROJECT SUMMARY Neuropathology continues to impact many people with HIV (PWH) regardless of antiretroviral (ART) mediated viral suppression, which contributes to significant morbidity and mortality. Specifically, ART-suppressed HIV infection is associated with reduced brain volume, ongoing neuroinflammation and subtle but sustained neurocognitive impairment. The mechanisms underlying neuropathology still remains unclear but likely relate to both local viral reservoirs in the brain and systemic factors associated with gut damage, which is a hallmark of HIV infection that is not ameliorated by ART-suppression alone. Importantly, using physiologically relevant non- human primate (NHP) models of both HIV infection and gut damage we have demonstrated in pilot studies that gut damage alone can induce neuroinflammation, identifying a highly novel pathway in HIV neuropathology. However, the specific mechanisms by which gut damage can induce neuropathology, including direct pathways propagated by damage to the enteric nervous system (ENS), remains unclear and the key aim of this study. In this prospective NHP proposal we will utilize novel cohorts of either SIV-infected (n=24) or SIV-uninfected (n=16) rhesus macaques (RMs) with experimentally induced chronic colitis paired with high-dimensional spatial approaches (i.e., SIV DNA/RNAscope, high-plex immunofluorescent imaging and spatial transcriptomics) to systematically and comprehensively define the mechanisms by which gut damage drives neuroinflammation. Importantly, our approach using complementary NHP models allows us to uniquely define the specific contribution of gut damage induced by both viral and non-viral sources to neuroinflammation, thus informing on the impact of these parameters in PWH. All regions of the brain, including all lobes, basal ganglion, hippocampus and brain stem as well as gut, lymph nodes, plasma, CSF and PBMCs will be collected from all animals, thus, providing a full assessment of the gut-brain axis. Specifically, in Aim 1 we will characterize the impact of experimentally induced colitis on the local gut microenvironment, including the ENS in SIV-uninfected RMs treated with cycles of dextran sulfate sodium (DSS), which we have validated as a model that mimics SIV- induced gut damage. Full characterization of neuroinflammation will extend on our preliminary data to define the relationship between gut damage, ENS dysfunction, systemic inflammation and neuroinflammation in the brain. In Aim 2 we will further define the impact of SIV infection on gut damage, ENS function and neuroinflammation. SIV infected NHPs treated with ART during either acute (9 dpi) or chronic (56 dpi) SIV infection to determine whether early ART initiation can ameliorate impacts on CNS neuroinflammation. Together, these studies will provide the most comprehensive analysis of the mechanisms by which gut damage induces neuroinflammation and how SIV infection can modulate these interactions at a cellular level in vivo. Understanding the mechanisms by which gut damage induces neuropathology will inform therapeutic approaches targeting the gut to improve brain health for both PWH and other sufferers of neuropathology.
