CD4+ T cells undergoing latency reversal induced by antigen-presenting dendritic cells display unique transcriptomic and TCR profiles 4359

Abstract Description While antiretroviral therapy (ART) for HIV infection effectively prevents disease progression, the persistence of a replication-competent latent viral reservoir requires strict lifelong adherence to these medications. Numerous strategies to achieve lasting immunologic control of HIV have been proposed, including the concept of ‘kicking’ the latent virus into active replication during ART to expose the infected cells for a subsequent immune ‘kill.’ We developed an approach using autologous monocyte-derived dendritic cells (MDC) presenting CMV-derived helper antigen to induce HIV latency reversal in CD4+ T cells from people living with HIV. We demonstrate that responding T cells harboring HIV can be isolated by flow sorting based on differential surface expression of CD4, which is downregulated upon active HIV transcription, as indicated by a 15-20-fold enrichment of integrated HIV-1 DNA content in CD4low sorted cells. Transcriptomic profiling of these CD4low cells revealed upregulation of IL10, CCL5, PDCD1 (PD-1), CCL4, and genes associated with TCR activation including TNFRSF9 (4-1BB). Importantly, CD4low cells had unique TCR sequences with evidence of clonal expansion, displaying CDR3 sequences associated with known CMV-specific TCRs. These data provide mechanistic insights into MDC-induced HIV latency reversal and support the inclusion of heterologous CMV helper antigen as a therapeutic strategy to precisely expose and target the HIV reservoir. Funding Sources Supported by NIH/NIAID R01AI152655; NIH/NHLBI U01HL146208; NIH/NIAID P30AI036219 Topic Categories Viral Immunology (VIR)