R01AI161803

Natural Killer Cell Engineering to Target the HIV Reservoir - Abstract

HIV continues to be a global health concern that has claimed the lives of millions. Although anti-retroviral therapy (ART) slows disease progression, ART is not curative due to certain reservoirs of replication-competent virus that persist during therapy. Therefore, if ART is stopped, then the virus can emerge from these reservoirs and rapidly spread, causing renewed progression towards AIDS. In addition, life-long use of ART is associated with issues related to cost, medical compliance, and adverse drug events.

One strategy for clearing the reservoir of latently infected cells is to use a kick and kill approach, in which latent cells are "kicked" or activated from latency, and then concurrently cleared or "killed". Latency reversal agents (LRA) can "kick" or induce HIV expression from latent cells, but thus far only a subset of activated latent cells die.

Natural Killer (NK) cells hold great promise as killing agents for HIV-infected cells as they re-emerge from latency due to their innate anti-viral recognition and cytotoxic function. The goal of this research project is to develop new methods to enhance the intrinsic killing activity of NK cells and to develop NK cell-based kick and kill strategies to reduce the need for life-long ART by decreasing or eliminating latent viral reservoirs.

We intend to approach this proposal by using cutting-edge technology to engineer the enhanced survival and anti-viral function of NK cells, sophisticated humanized mouse models of HIV latency, and innovative tools to measure and study the effect of our treatments on the HIV reservoir. We will test our overall hypothesis that a kick and kill approach will decrease or eliminate the latent reservoir in the following aims:

1) Engineer NK cells to enhance their elimination of HIV-infected cells using an innovative non-viral mRNA transfection technology.
2) Investigate the effect of novel latency reversal agents (LRAs) in combination with modified NK cells on HIV reservoirs in a humanized mouse model of HIV latency.

This proposal utilizes Dr. Jerome Zack's (lead PI, UCLA) extensive background in HIV latency and animal modeling, Dr. Catherine Blish's (dual-PI, Stanford) expertise in NK cell immunobiology and cellular manipulation, and includes a unique collaboration with Dr. Paul Wender (Stanford), an expert in chemical synthesis, who has developed a globally unique library of latency reactivating agents (LRAs) with unprecedented latency reversal capabilities and expanded tolerability that will be tested individually and in synergistic combinations with NK cells.

Together, we hope to fully harness the potential of NK cellular therapies and develop LRA and NK cell combination therapeutic approaches to provide patients with sustained virologic remissions or complete viral eradication.

Los Angeles University Of California

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.

93.242 - Mental Health Research Grants

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

National Institute of Mental Health (NIMH) [HHS - NIH]

Los Angeles, California 900958348 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 2933% from $125,000 to $3,790,684.