Innate Immune Memory in Myeloid Cells Can Reactivate Latent HIV-1 from HAART suppressed PBMCs of PLWH by Enhanced Cross Talk with Lymphoid Cells 9274

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Abstract Description We used established innate immune memory-inducing stimuli to study the reactivation of HIV from latently infected cells. Inducing innate immune training activated transcription of HIV-1 genes from THP89GFP monocytic latent HIV reporter cells. Four out of 17 patients had detectable counts of HIV from PBMC-derived macrophages and demonstrated reactivation with all three training stimuli. We also found that trained macrophages in co-culture can directly induce reactivation of HIV from 2D10 cells, a T cell reporter line for latent HIV, suggesting an innate immune memory-induced crosstalk between macrophages and T cells. To further study this, we performed scRNA-seq and scATAC-seq in PBMCs of ART-suppressed PLWH. We identified enhanced cell-to-cell ligand-receptor cross talk specifically between trained myeloid cells and lymphoid cells. Training of myeloid cells in PBMCs of PLWH also led to enhanced expression of many genes among the known pathways of CD4/CD8 T cell, NK cell and B cell activation. This suggests that innate training of the PBMC myeloid compartment may also trigger an enhanced CD8 T cell or NK cell-mediated elimination of the HIV reservoir. Our studies suggest that induction of innate immune memory could be a viable approach to the reactivation of latently infected HIV-1 and could be developed as a novel therapeutic approach to facilitate the elimination of latent HIV reservoirs. Funding Sources This work was supported by the Intramural Research Program of NIAID, NIH and the Office of the AIDS Research at NIH. Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)

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