Investigating The Function Of NK Cells In HIV-1Infected Chinese Individuals

The human immunodeficiency virus (HIV) directly targets and devastates the host’s immune system, leading to serious infection. Recently, research found innate immunity played very important role in against HIV infection. Natural killer (NK) cells are important part of innate immunity, and are critically involved in combating HIV infection and infective cells. The ability of NK cells mediating protection against viral infection depends on the relative abundance of each subset, and the effects of NK subsets rely on the composition of receptors on the NK cell surface, including inhibitory NK receptors (iNKRs) and activating receptors. These receptors recognize relative ligands of target cells, and induce activating or inhibitory signal. NK cells could kill target cells and inhibit HIV-1replication, at least partly due to antibody-dependent cell-mediated cytotoxicity (ADCC). However, the roles of NK cells against infection are still under debate, and mechanisms are needed intensive research.In this study, we recruited treatment-naive HIV-1infected individuals, including45new infected,47chronic MSM (men who have sex with men) HIV-infected individuals,41chronic former plasma donors (FPD) and35healthy donors as control. Flow cytometry was used to determine the abundance of NK cell subsets, the expression levels of receptors, the ADCC responses of NK cells and HLA-1genotypes, and try to evaluate the correlation with controlling HIV-1viral replication, which may lead to a better understanding of HIV-1infection. In this study, compared with healthy control, cytotoxic subset of NK cells decreased and dysfunctional subset increased significantly from early HIV-1infection time of infected individuals (P<0.001). During HIV disease progression, total NK cells and immunoregulatory subset are also reduced. Cytotoxic subset varies in different infected status, which has correlation with CD4counts and viral load. During HIV infection, the balance of activating receptors and inhibitory receptors of NK cells is broken, and the expression level of NKG2C, NKG2A, NKP46are increased (P<0.001), but CD16and CD161are reduced (P<0.001). Moreover, NKG2A was negative associated with CD4counts, and CD161was negative associated with viral load in early time of HIV infection. In long term infected individuals, NKG2A and NKP46had negative correlation with CD4counts, but CD158a had positive correlation with viral load.In addition, it is shown that there was specific ADCC responses to env peptides pool in early time of HIV infection (<3months). Though the responses were low, we still observed that these responses were negative associated with viral load at that time. But during longer infected time, antibodies are much more matural, so the higher ADCC responses were observed. But in the later infection status, NK cells become dysfunctional, which resulted in a lower ADCC reponses. In this study, the individuals of advanced infected status had lower ADCC reponses than elite controllers. However, ADCC responses still had correlation with CD4counts and viral load.Furthermore, we analysed the correlation between NK cell receptors and ADCC responses, and found the negative correlation between NKP46, CD158a, NKG2A and ADCC responses in early time of HIV infection. In long term infection, CD16and NKG2C had positive correlation with ADCC, but CD161had negative correlation with ADCC. Compare with non-controllers, the elite controllers had relative common expression level of NK cell receptor and higher specific ADCC responses to env peptides pool.This study analysed the HLA-1molecular genotypes, since KIR of NK cell receptor could combine HLA to control HIV infection. The results showed that the infected individuals who carry the HLA-A*30/B*13/Cw*06haplotype had lower viral load, and a negative association between ADCC responses and viral load in those who carry the HLA-A*30/B*13/Cw*06haplotype was also observed. The reason may be these specific HLA haplotype could combine KIR, so induce NK cell immunity.So we get the conclusion:the changes of cytotoxic subset and dysfunctional subset, dysfunctional expression of NKG2A and CD161, changes of ADCC responses reduced by NK cells, and carry the HLA-A*30/B*13/Cw*06haplotype have correlation with HIV disease progression.The study evaluated the function of NK cells immunity against HIV infection and disease progression, which may provide helpful data into understanding of HIV-1pathogenesis and immune mechanisms, facilitating anti-virus drugs development and vaccine evaluation.