Fine Mechanisms of Adaptive NK Cell Formation Against HIV and SIV

目前旨在预防、控制或根除艾滋病毒的大多数战略依赖于利用效应功能

The majority of current strategies aiming to prevent, control or eradicate HIV rely on harnessing effector functions of cytotoxic T cells, helper T cells, B cells and antibodies to attack HIV and HIV-infected cells. However, natural killer (NK) cells might represent the ideal subset of antiviral effector cells to promptly and potently respond to HIV exposure. Classically, NK cells are viewed as nonspecific effector cells of the innate immune system that play critical roles in defense against viral infections, including HIV. Besides their ability to rapidly eliminate virus- infected cells without the need for prior antigen sensitization, several independent studies from the past 12 years have demonstrated that subsets of murine, non-human primate (NHP) and human NK cells are capable of adaptive immune functions, including antigen-specificity and recall responses. Our laboratories provided the first clear evidence of antigen-specific NK cell memory in a primate species, elicited by HIV/SIV infection and vaccination. Preliminary data presented in this application now show that antigen-specific NK cell memory with potent antiviral functions develops upon exposure to HIV in humans and provide the first mechanistic evidence for antigen-specific NK cell memory, strongly supporting a role for HLA-E and its activating ligand NKG2C in antigen-specific NK cell responses. Collectively, these findings suggest that antiviral functions of adaptive NK cells have tremendous potential to be exploited for vaccine design, curative or other therapeutic interventions against HIV. However, the most significant obstacles to harnessing adaptive NK cell functions is the opacity surrounding the mechanisms of their formation and their potential to mediate protection in primate species. In this study, we propose to address the overarching hypothesis that adaptive NK cell responses develop kinetically to inhibit SIV/HIV replication and use disparate mechanisms of MHC recognition and alternative epigenetic and metabolic programs through two focused yet independent Aims: (i) Define in vitro and in vivo mechanisms of MHC-E-restricted NK cell antigen specificity against HIV and SIV infections; and (ii) Delineate NK cell-specific molecular programs influencing adaptive NK cell formation against HIV and SIV. Taken together, these investigations will provide critical information on the development of antigen- specific memory NK cells against SIV/HIV and determine the capacity of this NK cell subset to control viral replication. If successful, these studies will identify clear pathways that could be exploited to further enhance adaptive NK cell antiviral activity in future HIV vaccine and/or cure strategies.