R01AI161816

Harnessing Adaptive NK Cell Transfer to Deplete Viral Reservoirs - Project Summary

Natural Killer (NK) cells provide an immediate defense against viruses and tumors by virtue of their ability to respond to infected or malignant cells without prior antigenic stimulation. This is accomplished through the integration of signals from activating and inhibitory NK cell receptors (ANKRs & INKRs). In humans and other primate species, these include C-type lectin receptors, such as CD94/NKG2A and CD94/NKG2C, and the highly polymorphic Killer-cell Immunoglobulin-like Receptors (KIRs), both of which interact with MHC class I ligands. These receptor-ligand interactions are fundamental to the ability of NK cells to differentiate healthy cells from unhealthy cells and provide a potential mechanism of specificity for the development of "NK cell memory".

NK cells can have a significant impact on HIV-1 infection. KIR and HLA class I polymorphisms have been identified that are associated with lower viral loads and slower courses of disease progression, and certain NK cell subsets can kill HIV-infected cells in culture. Thus, NK cell-based therapies represent a promising approach for targeting HIV-infected cells and reducing the size of viral reservoirs.

We hypothesize that viral peptides bound by the MHC class I ligands of ANKRs are critical to NK cell recognition and killing of HIV/SIV-infected cells, and that the adoptive transfer of ex vivo activated NK cells in combination with latency reversal can deplete viral reservoirs in SIV-infected macaques on suppressive antiretroviral therapy (ART).

In Aim 1, we will determine the contribution of viral peptides bound by MHC class I ligands of ANKRs to NK cell recognition of HIV- and SIV-infected cells. These studies will utilize high-throughput cellular assays to rapidly screen viral peptides for MHC class I interactions with ANKRs and to identify substitutions that disrupt these interactions. The corresponding changes will be introduced into HIV-1 and SIV to assess their impact on NK cell responses to virus-infected cells.

In Aim 2, we will assess the capacity of ex vivo expanded NK cells in combination with latency reversal to deplete viral reservoirs in SIV-infected, ART-suppressed rhesus macaques. This aim will take advantage of barcoded SIV and a potent new latency reversal agent to compare, with maximal sensitivity, the ability of autologous versus allogeneic NK cell transfer to reduce the rate of viral reactivation after discontinuing ART.

In Aim 3, we will test the hypothesis that the depletion of viral reservoirs by adaptive NK cell transfer can be enhanced by an Env-specific antibody with antibody-dependent cellular cytotoxicity against SIV-infected cells. This aim will use a similar approach as Aim 2 to determine the extent to which coupling NK cell effector function to the unparalleled specificity of antibodies can maximize reservoir depletion.

These unprecedented studies will provide a better understanding of the role of viral peptides in NK cell recognition of HIV- and SIV-infected cells and an important proof-of-concept for the development of NK cell therapies to eradicate HIV-1 reservoirs in chronically infected individuals.

University Of Wisconsin System

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]

Madison, Wisconsin 53715 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 399% from $764,536 to $3,812,634.