Innate Immune Memory induced by MDP, B-glucan or SYK Inhibition Accelerates Trained Immunity-Based Elimination of HIV Infected Cells from PBMCs of PLWH 9273

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Abstract Description HIV virus can persist latently in CD4+ T-cells and tissue-resident macrophages. This necessitates lifelong antiretroviral therapy (ART) for people living with HIV (PLWH). Reactivation of latent HIV results in killing of infected cells by immune cells. Studies with latency reactivating agents have shown that reactivation alone is not sufficient for the elimination of the HIV reservoir. HIV latency is associated with histone methylation mediated chromatin condensation at viral integration sites. Innate immune memory induced in macrophages by muramyl dipeptide, ß-glucan and Syk inhibition has been shown to relieve chromosome condensation through epigenetic rewiring at immune effector gene loci, thereby increasing phagocytosis, antigen presentation, and lymphoid cell activity. We trained PBMCs of ART-suppressed PLWH in the presence of matched autologous sera to test whether this could lead to specific killing of the HIV infected cells. qPCR analysis with the IPDA HIV reservoir assay showed that training with autologous sera could not only enhance the reactivation of viral RNA transcription, but could also lead to HIV reservoir reduction, potentially through NK cell and CTL activation, enhanced antigen presentation, and phagocytosis by trained macrophages and dendritic cells. Our data highlight a new therapeutic approach for PLWH where training of myeloid cells could both reactivate latent HIV transcription and reduce the viral reservoir through CTL and NK cell dependent killing. Funding Sources This work was supported by the Intramural Research Program of NIAID, NIH and the Office of AIDS Research at NIH. Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)