Natural Killer Cells And γδ T Cells In Immunodefense Against HIV-1

Acquired Immunodeficiency Syndrome (AIDS) caused by Human ImmunodeficiencyVirus (HIV) could devastate immune system in human, which lead to some seriousinfections. AIDS, which spread worldwide, has become one of the most severeinfectious diseases to human health. The failure to develop an effective HIV vaccineor HIV drug highlights the importance to strength the researches on the immuneprotective mechanism in HIV infection.Recently, researchers found innate immunitymight play quite an important role in against HIV infection. Natural killer (NK) cellsand γ T cells, both as important part of innate immunity, are critically involved incleaning virus-infected cells. In our research, we focused on not only how NK and γT cells exert their function through directly killing in innate immune response, butalso on their capacity to mediate ADCC in adaptive immunity during HIV infection.Viral inhibition assay (VIA) directly reflects the ultimate effector function of cells toinhibition virus. In our research, we established and optimized VIA to detect thecapacity of NK cells and γ T cells to inhibit HIV virus. There were three methodsapplying in the assay, including: detection of percentage of HIV-infected CD4T cellsby flow cytometry, also referred as intracellular p24staining; detection of p24proteins in supernatant by p24ELISA; detection of HIV viral RNA in supernatant byquantification of viral RNA (vRNA). Although the three methods correlated with eachother, p24ELISA and vRNA quantification were better adapted to categorize viralinhibition response than intracellular p24staining. Importantly, we found that bothNK cells and γ T cells could efficiently inhibit HIV replication in autologous CD4Tcells ex vivo, and the inhibition was also dependent on the ratio of effector and targetcells. Besides, with the significant inhibition of HIV replication by NK cells fromhealthy subjects, the autologous CD8T cells showed little efficacy of inhibition.These data directly show the capacity of NK cells and γ T cells to fight against HIVin terms of their characters as innate immune cells. Increasing evidence indicates that antibody-dependent cellular cytotoxicity (ADCC)contributes to the control of HIV/SIV infection. Although some research in humanstudy have suggested the close correlation between NK-cell mediated ADCC and HIVdisease progression, little is known about the ADCC function of NK cells innon-human primate model. Here we demonstrated that ADCC function of NK cellswas significantly compromised in chronic SIV/SHIV infection, correlating closelywith the expression of FcγRIIIa receptor (CD16) on NK cells. CD32, another class ofIgG Fc receptors, was identified on NK cells with higher expression in the infectedmacaques and the blockade of CD32impacted the ability of NK cells to respond toantibody-coated target cells. The inhibition of matrix metalloproteases (MMPs), agroup of enzymes normally involved in tissue/receptor remodeling, could restore NKcell-mediated ADCC with increased CD16expression on macaque NK cells. Thesedata offer a clearer understanding of NK cell-mediated ADCC in rhesus macaques,which will allow us to evaluate the ADCC repertoire arising from preclinicalvaccination studies in non-human primates and inform us in the future design ofeffective HIV vaccination strategies.Growing evidence has suggested that HIV infection severely damages the Vγ22(V2) T cells that play an important role in the first-line host response to infectiousdisease. However, little is known about V2T cell-mediated ADCC in HIV disease.We found that although the CD16+V2T cell subset hardly participated inphosphoantigen responses dominated by the CD16-V2T cell subset, the potency ofthe ADCC function of V2Tcells was correlated with the frequency of the CD16+subset. Thus, two distinct and complementary V2T cell subsets discriminated byCD16were characterized to explore the respective impacts of HIV-1infection onthem. HIV-1disease progression was not only associated with the phosphoantigenresponsiveness of the CD16-V2subset, but also with the ability of the CD16+V2subset to kill antibody-coated target cells. Furthermore, both of the two V2functional subsets could be partially restored in HIV-infected patients with antiretroviral therapy. Notably, in the context of an overall HIV-mediated V2T celldepletion, despite the decline of phosphoantigen-responsive CD16-V2cells, CD16+V2cell-mediated ADCC was not compromised but exhibited a functional switchwith dramatic promotion of degranulation in the early phase of HIV infection andchronic infection with slower disease progression. Our study reveals functionalcharacterizations of the two V2T cell subsets with different activation pathwaysduring HIV-1infection and provides a rational direction for activating the CD16+V2T cells capable of mediating ADCC as a means to control HIV-1disease.