The expression of CD39 on NK cells relates to poor HIV-1 suppression in treatment-naïve HIV-1-infected individuals: Association with elevated IL-10 secretion and TIGIT co-expression

CD39 exerts an inhibitory effect on tumour progression by impairing the cytotoxic capacity of natural killer (NK) cells against Cancer cells. However, the impact of CD39 expression on the non-cytolytic functions of NK cells in treatment-naïve human immunodeficiency virus type 1 (HIV-1)-infected individuals remains poorly understood. In this study, thirty-four individuals with acute HIV-1 Infection (AHI), thirty-eight with chronic HIV-1 Infection (CHI), and twenty-four HIV-1-negative healthy controls (HC) were enrolled to explore the role of CD39 expression on NK cells in HIV-1 suppression at different Infection stages. Flow cytometry was employed to analyze the immune phenotype and functional characteristics of NK cells. We found that CD39 expression on NK cells was significantly upregulated following HIV-1 Infection, and its positive rate was positively associated with HIV-1 viral load in both AHI and CHI individuals. Compared with CD39^- NK cells, CD39⁺ NK cells exhibited reduced activation; in AHI individuals, the activation level of CD39⁺ NK cells was positively associated with HIV-1 viral load but inversely correlated with CD4⁺ T-cell counts. In CHI individuals, the interleukin-10 (IL-10)-producing capacity of total NK cells, CD39⁺ NK cells, and CD39^- NK cells was enhanced and positively correlated with HIV-1 viral load. Additionally, across the AHI and CHI groups, the overall IL-10-secreting ability of NK cells was positively correlated with the frequency of CD39⁺ NK cells. In both AHI and CHI individuals, CD39⁺ NK cells showed lower T-cell immunoglobulin and ITIM domain (TIGIT) expression than CD39^- NK cells, while the CD39⁺TIGIT⁺ NK cell subset displayed significantly stronger IL-10-secreting capacity. POM-1, an inhibitor of CD39 ectonucleotidase activity, could enhance IL-10 secretion by NK cells in both HIV-1-infected individuals and the majority of healthy controls, but attenuate interferon-γ (IFN-γ) secretion by NK cells in HIV-1-infected individuals. In contrast, the CD39-blocking antibody A1 reduced IFN-γ secretion without affecting IL-10 secretion by NK cells in both HIV-1-infected individuals and healthy controls. Our findings reveal a novel CD39⁺ NK cell-associated mechanism that contributes to ineffective HIV-1 control, and suggest that CD39, alone or combined with TIGIT, may serve as a promising target to restore Antiviral NK cell function in treatment-naïve individuals living with HIV-1.

CD39; HIV-1 infection; IL-10; Natural killer cells (NK cells); T-cell immunoreceptor with Ig and ITIM domain (TIGIT).