Heterogeneity of Latency Establishment in the Different Human CD4+ T Cell Subsets Stimulated with IL-15

HIV integrates into the host genome, creating a viral reservoir of latently infected cells that persists despite effective antiretroviral treatment. CD4-positive (CD41) T cells are the main contributors to the HIV reservoir. CD41 T cells are a heterogeneous population, and the mechanisms of latency establishment in the different subsets, as well as their contribution to the reservoir, are still unclear. In this study, we analyzed HIV latency establishment in different CD41 T cell subsets stimulated with interleukin 15 (IL-15), a cytokine that increases both susceptibility to infection and reactivation from latency. Using a dual-reporter virus that allows discrimination between latent and productive infection at the single-cell level, we found that IL-15-treated primary human CD41 T naive and CD41 T stem cell memory (TSCM) cells are less susceptible to HIV infection than CD41 central memory (TCM), effector memory (TEM), and transitional memory (TTM) cells but are also more likely to harbor transcriptionally silent provirus. The propensity of these subsets to harbor latent provirus compared to the more differentiated memory subsets was independent of differential expression of pTEFb components. Microscopy analysis of NF-κ B suggested that CD41 T naive cells express smaller amounts of nuclear NF-κ B than the other subsets, partially explaining the inefficient long terminal repeat (LTR)-driven transcription. On the other hand, CD41 TSCM cells display similar levels of nuclear NF-κB to CD41 TCM, CD41 TEM, and CD41 TTM cells, indicating the availability of transcription initiation and elongation factors is not solely responsible for the inefficient HIV gene expression in the CD41 TSCM subset.