R01AI161010

Fine Mechanisms of Adaptive NK Cell Formation Against HIV and SIV

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 are 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.

Duke University

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Durham, North Carolina 27705 United States

Single Zip Code

Harnessing Natural Killer (NK) Cells to Prevent, Control, or Eradicate HIV (R01 Clinical Trial Not Allowed) (RFA-AI-20-016)

Amendment Since initial award the total obligations have increased 459% from $881,222 to $4,922,128.