Transcriptional Control of HIV Latency in Hematopoietic Stem and Progenitor Cells

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Abstract HIV establishes a persistent infection despite the host immune response and treatment with antiretroviral therapy (ART). This is due to the establishment of latent infections in a small subset of cells – predominantly resting memory T lymphocytes (TRM), which can survive for decades, and from which virus can rebound with interruption in therapy. In addition to CD4+ T cells, we have demonstrated that HIV can also infect and establish latent infections in CD4+ hematopoietic stem and progenitor cells (HSPCs). HSPCs are extremely long-lived, have the potential for self- renewal, and importantly, contribute to viremia in patients that have maintained ART for many years. In vitro studies of HIV latency demonstrate immediate latency establishment in HSPCs in contrast to a period of weeks required for most T cell latency models. Some of the mechanisms that control latency in CD4+ T cells have been well established and primarily involve epigenetic factors such as histone methylation or lack of recruitment of an activating factor to the 5’ long terminal repeat (LTR). Whether silencing of HIV is established similarly in HSPCs has yet to be determined. Discovering the biochemical factors that control latency reversal as well as markers that identify latently infected cells could facilitate targeting or activation of latently infected cells and elimination of the viral reservoir. Our recent work suggests that the global transcriptomic and epigenetic changes that occur during hematopoietic differentiation affect viral latency and activation. We have found that latency in the most primitive HSPCs is relatively resistant to reversal by histone deacetylase inhibitors. Moreover, we generated intriguing preliminary data suggesting the novel hypothesis that unique stem cell specific mechanisms play important roles in silencing HIV gene expression in HSPCs. To test this hypothesis, we will use a combination of single-cell, biochemical, and molecular biology techniques in addition to computational approaches to better define the characteristics of latently versus actively infected HSPCs with the following aims: (1) determine the transcriptomic and epigenomic landscape of latent versus actively infected HSPCs, and (2) determine the extent to which integration site and local chromatin structure play a role in silencing HIV proviral genomes in HSPCs. Together, these aims will identify DNA and RNA biomarkers of latency, uncover HSPC specific silencing mechanisms and produce an integrated transcriptomic and epigenomic atlas of the HIV reservoir in HSPCs.