Background
Viral reservoir presents a significant challenge in HIV-1 cure. Studies indicate that dendritic cells may limit HIV-1 reservoir by bolstering CD8+ T cell function via the IL-15 pathway and facilitating the expansion of virtual memory CD8+ T cells (TVM). 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.
Methods
Peripheral blood mononuclear cells (PBMCs) were obtained from individuals 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 in a two-layer transwell model. To assess the levels of reservoir reactivation and CD8+ T cell functionality, flow cytometry was employed to measure changes in HIV-1 p24 protein levels in CD4+ T cells, cytokine/chemokine levels in CD8+ T cells, TVM subpopulation proportions, and IL-2Rβ receptor expression on TVM cells. Fluorescence quantitative PCR measured changes in HIV-1 integrated DNA levels to assess reservoir size.
Results
In vitro, Tα1 stimulation of MoDCs resulted in significant secretion of IL-15/RA complexes (p<0.001). This interaction with IL-2Rβ/γ receptors on T cells enhanced the intracellular secretion of CCL3/5, IFNγ, and TNFα in CD8+ T cells (p<0.05), as well as proliferation of TVM subpopulation (p=0.013), inhibited p24 levels in CD4+ T cells (p=0.004), and reduced HIV-1 integration DNA levels (p=0.012). The decreased degree of p24 level was negatively correlated with the secretion of intracellular cytokines in CD8+ T cells and the increase of TVM proportions (p<0.05). However, these effects were observed in PBMCs from immunological responders rather than nonresponders (INR). Neither Tα1 nor rhIL-15 stimulation altered the frequency of TVM cells in INR (p=0.126) or the expression of surface IL-2Rβ receptors (p>0.05), indicating impaired responsiveness of these subsets to IL-15 signaling.
Conclusions
This study demonstrate that Tα1 enhances CD8+ T cell function, promotes TVM proliferation, and suppresses reservoir size and reactivation via IL-15 pathway activation in dendritic cells. Impaired IL-15 signaling responsiveness in INRs may contribute to poor reservoir control, highlighting a potential therapeutic target.