A-108 The Contribution of memory CD4+ T cell subset phenotype to latency reversal efficiency

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The latent HIV reservoir persists in individuals on ART predominantly in memory CD4+ T cells, a heterogeneous population comprised of central memory (CM), transitional memory (TM) and effector memory (EM) subsets. Current HIV eradication strategies that aim to reverse latency in this heterogeneous pool of cells have had limited success. To characterize HIV latency reversal in all memory CD4+ T cell subsets that contribute to the HIV reservoir in vivo, we developed LARA (Latency and Reversion Assay), a primary cell based in vitro model of HIV latency. To identify pathways associated with latency reversal in each subset, we exposed latently infected cells from both HIV-infected individuals and LARA to different classes of latency reversing agents (LRAs). Memory subsets showed distinct responses that resulted in varying efficiencies to the LRAs tested. Importantly, the most effective LRAs triggered the differentiation into cells that expressed an EM phenotype. Transcriptional profiling of CD4+ T cells from HIV-infected individuals exposed to bryostatin, the LRA that showed the highest latency reversal, identified several EM specific pathways that were significantly upregulated in both the CM and EM subsets, including genes encoding for cytokines and effector molecules such as IFN-γ, IL-2, IL-4, and TNF. Together, these results support LRA exposure triggering differentiation toward an EM subset phenotype to be linked to higher latency reversal efficiency. Identification of these pathways is a critical prerequisite to understand factors that influence latency reversal in vivo as well as contributing to the most effective design of regimens capable of comprehensive reactivation of the HIV reservoir in eradication strategies.

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