AUTHOR=Zhang Xin , Lu Xiaofan , Cheung Allen Ka Loon , Zhang Qiuyue , Liu Zhiying , Li Zhen , Yuan Lin , Wang Rui , Liu Yan , Tang Bin , Xia Huan , Wu Hao , Zhang Tong , Su Bin TITLE=Analysis of the Characteristics of TIGIT-Expressing CD3−CD56+NK Cells in Controlling Different Stages of HIV-1 Infection JOURNAL=Frontiers in Immunology VOLUME=12 YEAR=2021 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.602492 DOI=10.3389/fimmu.2021.602492 ISSN=1664-3224 ABSTRACT=

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.