Decoding epigenetic scars of smoldering neuroinflammation and CNS complications in people with HIV

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PROJECT SUMMARY/ABSTRACT The goal of this proposal is to unravel mechanisms driving abnormal immune activation and cognitive impairment in people living with HIV (PLWH) through the lens of epigenetic programming. Despite overall advances in lifespan and health for PLWH who are on suppressive ART, a subset of individuals on ART continue to demonstrate neuroimmune abnormalities and associated clinical neurological syndromes including cognitive complications. Cerebrospinal fluid (CSF) studies are a window into the CNS of PLWH, revealing a role for abnormal myeloid cell activation and persistence viral replication in the CNS, despite apparent systemic viral suppression with ART. Our own single cell genomic studies of fresh CSF cells from PLWH have shown that a rare microglia-like myeloid cell population resides in the CSF in PLWH; that these cells are linked to HIV disease status; and that these myeloid cells can harbor HIV DNA. Additionally, our research has shown that epigenetic features of myeloid cells are rapidly altered in HIV infection and this aberrant myeloid epigenetic state associated with HIV infection persists despite the immediate initiation of ART during acute HIV infection. However, despite myeloid cells being recognized as crucial cellular mediators of CNS abnormalities in PLWH, the epigenetic landscapes of CNS myeloid and other immune cells in PLWH remain uncharted. Our central hypothesis is that HIV leaves epigenetic “scars” at regulatory regions of proinflammatory gene networks in distinct CSF myeloid cell subsets, contributing to HIV-related cognitive impairment despite ART. This hypothesis will be tested in our established HIV Associated Reservoirs and Comorbidities Study (HARC) cohort at Yale that includes large volume lumbar puncture from study participants with and without HIV and will be further explored utilizing postmortem brain specimens from the National NeuroAIDS Tissue Consortium (NNTC). In PLWH, we will longitudinally assess fresh CSF myeloid and T cell single cell epigenetic and transcriptional cell states over the course of ART treatment and ask whether there is damage to the epigenomes of CSF myeloid and T cells sustained during HIV infection that persists over time as epigenetic “scars”. Using machine learning, we will then assess for an association between epigenetic perturbations in PLWH and CNS outcomes, including cognitive impairment and abnormal CSF soluble biomarkers of inflammation and neuronal injury. We will also explore single cell epigenetic cell states of myeloid and glia in postmortem brain tissues from choroid plexus and periventricular zones of HIV-infected individuals who died on suppressive ART and matched controls. Lastly, we will apply an innovative new single cell assay for multifactorial chromatin profiling to assay histone modifications. These proposed, in-depth, multiomic single cell analyses of distinct myeloid cell subsets in the CNS and blood, combined with cognitive assessments, will reveal the effects of HIV infection on immune cell epigenomes, and will uncover transcriptional and epigenetic states most strongly related to cognitive complications in PLWH. The results will advance efforts to biotype CNS complications in PLWH based on immune and viral pathogenesis.