Thymosin α1-induced secretion of the IL-15/RA complex by THP-1-derived dendritic cells restrains HIV latency <i>in vitro</i>.
Thymosin α1 may enhance immune responses against HIV-1, but findings are based on in vitro studies and limited to immunological responders.
Where it sits
this study against the rest of the thymosin alpha-1 corpusSummary and findings
This study investigates the effects of Thymosin α1 (Tα1) on immune responses in PBMCs from people living with HIV-1. Tα1 stimulation of mature monocyte-derived dendritic cells (MoDCs) led to significant immune responses, including increased secretion of the IL-15/RA complex and enhanced CD8+ T cell functionality. Notably, Tα1 was associated with reduced HIV-1 integrated DNA levels.
Abstract
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<sub>VM</sub> 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<sub>VM</sub> 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.
Background
The viral reservoir is a major obstacle in achieving a cure for HIV-1. Previous studies indicated that Thymosin α1 (Tα1) may play a role in restricting this reservoir through the IL-15 pathway. This study aims to elucidate the mechanisms by which Tα1 influences immune responses in the context of HIV-1.
Methods
The study utilized peripheral blood mononuclear cells (PBMCs) from people living with HIV-1 (PLWH). THP-1 cells were differentiated into mature monocyte-derived dendritic cells (MoDCs) and co-cultured with PBMCs under various conditions. Primary outcomes included intracellular HIV-1 p24 levels and reservoir size, while secondary outcomes included CD8+ T and NK cell functionality.
Results
Tα1 stimulation of MoDCs resulted in a significant immune response, with a notable secretion of the IL-15/RA complex (p<0.001). This interaction enhanced intracellular secretion of CCL3/5, IFN-γ, and TNF-α in CD8+ T cells (p<0.05), which in turn inhibited p24 levels in CD4+ T cells (p=0.002) and reduced HIV-1 integrated DNA levels (p=0.012).
Interpretation
These findings suggest that Tα1 enhances CD8+ T cell function and suppresses reservoir size through IL-15 pathway activation, which aligns with previous literature indicating the importance of immune modulation in HIV-1 management. However, the clinical significance of these findings is uncertain due to the small sample size and the focus on immunological responders only, limiting broader applicability.
Key findings
- Secretion of IL-15/RA complex, p<0.001.
- Inhibition of p24 levels in CD4+ T cells, p=0.002.
- Reduction of HIV-1 integrated DNA levels, p=0.012.
- Increased secretion levels of IFN-γ, TNF-α, and GZMB in NK cells, p<0.05.
- Alterations inversely associated with reservoir size and reactivation.
Limitations
- Focus on PBMCs from immunological responders only.
- In vitro study, not fully replicating in vivo conditions.
- Small sample size may limit generalizability.