Inhibition of TIGIT on NK cells improves their cytotoxicity and HIV reservoir eradication potential.

Abstract

The latent human immunodeficiency virus (HIV) reservoir presents the biggest obstacle to curing HIV chronic infection. Consequently, finding novel strategies to control the HIV reservoir is critical. Natural killer (NK) cells are essential for antiviral immunity. However, the influence of NK cell subsets and their associated inhibitory or activating receptors on their cytotoxicity toward the HIV reservoir has not been fully studied. We investigated the relationship between the percentage of NK cells or NK cell subsets and the HIV reservoir. Our results indicated that the percentage of CD56^-CD16⁺ NK cells was positively associated with HIV reservoir size (i.e., HIV DNA, HIV msRNA, or HIV usRNA). Additionally, we observed that the percentage of IFN-γ⁺ NK cells was inversely related to the HIV reservoir. Furthermore, the expression of TIGIT on NK cells, particularly CD56^-CD16⁺ and CD56^dim NK cell subsets, positively correlated with the HIV reservoir. Notably, individuals with higher percentage of TIGIT⁺ NK and lower percentage of CD226⁺ NK cells exhibited larger HIV reservoir. Mechanistically, we discovered that TIGIT could inhibit the PI3K-Akt-mTOR-mTORC1 (s6k) signaling pathway to decrease the production of IFN-γ in NK cells. Importantly, inhibiting TIGIT in NK cells enhanced their ability to eliminate reactivated latently infected CD4⁺ T cells. Our experiments underscored the crucial role of NK cells in controlling the HIV reservoir and suggested that TIGIT serves as a promising target for enhancing the NK cell-mediated clearance of the HIV reservoir.

Importance: As a major barrier to human immunodeficiency virus (HIV) cure, HIV reservoir persist in viremia-suppressed infected individuals. NK cells are important antiviral cells, and their impact on reservoir has rarely been reported. We analyzed the relationship between the size of reservoir and NK cell subsets, inhibitory receptor TIGIT expression. Our analysis found that the percentage of CD56^-CD16⁺ NK cells was positively associated with HIV reservoir size. Furthermore, TIGIT expression on NK cells and CD56^-CD16⁺ NK cells or CD56^dim NK cells has a positive correlation with the HIV reservoir. TIGIT can inhibit the PI3K-Akt-mTOR-mTORC1 (s6k) signaling pathway to decrease the production of IFN-γ on NK cells. Blocking TIGIT in NK cells can enhance their ability to eliminate reactivated latently infected CD4⁺ T cells. Our study indicated that NK cells are critical to the control of the reservoir size, and TIGIT may be a target for enhancing the NK cell-mediated elimination of the reservoir.