Analysis of the Characteristics of TIGIT-Expressing CD3 - CD56 + NK Cells in Controlling Different Stages of HIV-1 Infection.

TIGIT expression on natural killer (NK) cells is associated with dysfunction during chronic HIV infection, but the phenotype and biological functions of these cells in the context of acute HIV-1 infection remain poorly understood. Here, 19 acutely infected HIV-1 patients traced at first, third and twelfth month, and age-matched patients with chronic HIV-1 infection were enrolled to investigate the phenotype and functions of TIGIT expression on NK cells. We found that TIGIT-expressing NK cells did not increase in frequency in the first, third and twelfth month of infection until chronic HIV-1 infection lasted over 2 years. The number of TIGIT ⁺ NK cells in acute infection was positively associated with HIV-1 viral load ( r = 0.53, P = 0.0009). CD96 was significantly upregulated on NK cells after acute infection for 1 month and in chronic infection over 2 years, while CD226 was downregulated in chronic infection over 2 years. Further, at different stages of infection, CD96 ^- CD226 ⁺ cells diminished among total NK cells, TIGIT ⁺ NK and TIGIT ^- NK cells, while CD96 ⁺ CD226 ^- cells expanded. Reduced CD96 ^- CD226 ⁺ cells and elevated CD96 ⁺ CD226 ^- cells among NK cells especially TIGIT ^- NK cells, had opposite associations with viral load in the first month of infection, as well as CD4 T-cell counts in including the twelfth month and more than 2 years of chronic infection. In both HIV-1-infected individuals and healthy donors, TIGIT was predominantly expressed in NKG2A ^- NKG2C ⁺ NK cells, with a significantly higher proportion than in NKG2A ⁺ NKG2C ^- NK cells. Moreover, the frequencies of TIGIT ⁺ NK cells were positively associated with the frequencies of NKG2A ^- NKG2C ⁺ NK cells in acute infection ( r = 0.62, P < 0.0001), chronic infection ( r = 0.37, P = 0.023) and healthy donors ( r = 0.36, P = 0.020). Enhanced early activation and coexpression of CD38 and HLA-DR in TIGIT ⁺ NK cells were detected compared to TIGIT ^- NK cells, both of which were inversely associated with the decrease in CD4 T-cell counts in both acute and chronic HIV-1 infection. The ability of TIGIT ⁺ NK cells to produce TNF-α, IFN-γ and CD107a degranulation substance were consistently weaker than that of TIGIT ^- NK cells in both acute and chronic infection. Moreover, the functionalities of TIGIT ⁺ NK cells were lower than those of TIGIT ^- NK cells, except for TNF-α ^- CD107a ⁺ IFN-γ ^- NK cells. These findings highlight the phenotype and functional characteristics of TIGIT-expressing NK cells which have poor capabilities in inhibiting HIV-1 replication and maintaining CD4 T-cell counts.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2021 Zhang, Lu, Cheung, Zhang, Liu, Li, Yuan, Wang, Liu, Tang, Xia, Wu, Zhang and Su.)