Thymosin α1-induced secretion of the IL-15/RA complex by THP-1-derived dendritic cells restrains HIV latency <i>in vitro</i>

Viral reservoir presents a significant challenge in HIV-1 cure. We previously observed that Thymosin α1 (Tα1) may restrict the reservoir through the IL-15 pathway. However, the precise mechanism remains to be fully elucidated. Peripheral blood mononuclear cells (PBMCs) were obtained from people living with HIV-1 (PLWH). In vitro, THP-1 cells were differentiated into mature monocyte-derived dendritic cells (MoDCs) and co-cultured with PBMCs under various conditions. Intracellular HIV-1 p24 levels, CD8+ T and NK cell functionality, and reservoir size were evaluated. In vitro, Tα1 stimulation of MoDCs resulted in significant immune response and secretion of IL-15/RA complex (<i>p</i> < 0.001). This interaction with IL-2 Rβ/γ receptors on T cells enhanced the intracellular secretion of CCL3/5, IFN-γ, and TNF-α in CD8+ T cells (<i>p</i> < 0.05), which inhibited p24 levels in CD4+ T cells (<i>p</i> = 0.002), and reduced HIV-1 integrated DNA levels (<i>p</i> = 0.012). Furthermore, the secretion levels of IFN-γ, TNF-α, and GZMB in NK cells and proportion of CD8+ T_VM cells significantly increased following co-culture. These alterations were found to be markedly inversely associated with reservoir size and reactivation. However, these effects were observed in PBMCs from immunological responders (CD4+ T cell count > 350 cells/µL) rather than nonresponders. Tα1 enhances CD8+ T cell function, promotes T_VM proliferation, and suppresses reservoir size and reactivation via IL-15 pathway activation in dendritic cells, which warrants testing in functional cure trials in the future.