Thymosin α1-induced secretion of the IL-15/RA complex by THP-1-derived dendritic cells restrains HIV latency <i>in vitro</i>.
This in vitro study investigated how Thymosin α1 (Tα1) may help reduce the HIV-1 viral reservoir by acting on immune cells. Researchers differentiated THP-1 cells into monocyte-derived dendritic cells (MoDCs) and co-cultured them with peripheral blood mononuclear cells (PBMCs) obtained from people living with HIV-1 (PLWH). The study found that Tα1 stimulation of MoDCs triggered secretion of the IL-15/IL-15 receptor alpha (IL-15/RA) complex, which was associated with enhanced CD8+ T cell and NK cell functionality — including increased secretion of IFN-γ, TNF-α, and granzyme B (GZMB) — along with reductions in intracellular HIV-1 p24 levels and integrated HIV-1 DNA. Notably, these effects were only observed in PBMCs from immunological responders (CD4+ T cell count >350 cells/µL) and not in non-responders. Key limitations include reliance on an in vitro cell line model (THP-1) rather than primary human dendritic cells, lack of an in vivo component, and the correlational nature of many associations. The authors suggest that Tα1's IL-15 pathway activation in dendritic cells could be a candidate mechanism for functional HIV cure strategies, warranting future clinical investigation.
Why this grade: All experimental findings were generated in a cell culture system using a THP-1 cell line and donor PBMCs, with no in vivo or controlled human trial component, limiting direct extrapolation to human efficacy.
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 ( p p p = 0.002), and reduced HIV-1 integrated DNA levels ( p = 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.
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