Mechanisms of Trained Immunity in HIV Immune Responses

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PROJECT SUMMARY / ABSTRACT Acute HIV infection is characterized by a robust innate immune response that determines the ultimate clinical disease course. Innate immune activation and transcriptional changes can persist beyond the acute infection period. Cells of the innate immune system can be reprogrammed or “trained” by prior exposures, and this lasting changes influence future immune responses. This phenomenon, termed trained immunity or innate immune memory, is epigenetically encoded, allowing stimulus-dependent transcription factors to bind not only to available cell type-specific enhancers, but also to previously inaccessible regions of the chromatin in the genome. Despite the importance of early innate responses in determining HIV disease course, the role of trained immunity in HIV infection has not been explored. Moreover, the effects of substance use on these early innate immune responses are not known. This project will leverage expertise in HIV immunology and substance use (Dr. Fulcher), innate immune memory epigenetic mechanisms (Dr. Cheng), and HIV immunology and cytotoxic T lymphocytes (Dr. Yang) to investigate mechanisms of trained immunity in shaping HIV immune responses and how HIV itself may reprogram innate immune cells. We hypothesize that exposure to certain stimuli during monocyte differentiation will lead to differential ability to produce cytokines and stimulate HIV-specific CD8+ T cell responses. In the setting of HIV infection, we hypothesize that HIV exposure induces monocyte reprogramming resulting in heightened secondary responses that may contribute to chronic inflammation and immune exhaustion. To test these hypotheses we will: (1) identify innate immune stimuli that train monocytes for optimal HIV-specific immune responses, including examining the effects of drugs of abuse on these responses and (2) characterize the innate immune memory produced by HIV infection and determine the viral factors and host signaling pathways required for training. We will train primary human monocytes, obtained from persons who do or do not use drugs, with different ligands during differentiation to macrophages then expose to HIV and compare outcomes using functional immune assays. Pathways will be interrogated using RNAseq. We will next train monocytes with HIV then examine epigenetic and transcription changes following secondary stimulus (LPS) using RNAseq and ATACseq. Results from these studies will advance understanding of how trained immunity shapes HIV immune responses, and how HIV may affect later immune responses. This knowledge can lead to novel immune targets for therapeutics to improve HIV prevention and treatment.