UM1AI164561

Reversing Immune Dysfunction for HIV-1 Eradication - Project Summary

Although the rate of new HIV infections has decreased, containment and eventual eradication of the HIV pandemic remains a top priority in contemporary biomedical research.

One of the major challenges to HIV cure is the need to restore normal immune function in order to effectively eliminate the established viral reservoir. We have assembled in RID-HIV: "Reversing Immune Dysfunction for HIV-1 Eradication", basic and clinical scientists with expertise in virology, immunology, microbiome biology, epigenetics, and systems biology. In addition, Merck Research Laboratories will invest significant intellectual, human, and material resources to complement the efforts of the academic scientists.

The RID-HIV collaboratory will collectively function to explore the underlying basis of the immune dysregulation in HIV-infected individuals and the impact it has on reservoir persistence and viral rebound control. We will test for the first time several innovative concepts, including identifying epigenetic mechanisms imprinted by the microbiome and host and bacterial metabolomes that prevent the development of effective innate and adaptive immune responses that can control the size, quality, and anatomical localization of the HIV reservoir.

The overarching goal of the RID-HIV collaboratory is to provide preclinical in vivo proof-of-concept for a therapeutic paradigm that encompasses immune restorative treatments, used in concert with enhanced viral reactivation and elimination strategies, in order to deliver an HIV-1 cure. We propose three highly integrated and complementary scientific research foci (RFS), to be supported by rigorous and iterative modeling of outcomes and shaped by our outreach to the HIV community.

In RF1, we will investigate the mechanisms whereby host- and microbiome-derived metabolites impact innate immune responses and influence the maintenance of the latent viral reservoir.

In RF2, we will pursue the hypothesis that in ART/ATI clinical cohorts, metabolites that govern innate immunity shape the adaptive immune responses that could prevent viral rebound upon treatment interruption. In addition, we will evaluate the capacity of engineered allogenic stem memory T cells to provide superior cognate help to promote the effector functions of antiviral CD8 T cells, and will assess the ability of FDA-approved and novel immune modulators to reset this baseline immune dysfunction and enhance the function of this novel cell therapy product.

In RF3, we will optimize a best-in-class latency reversal agent (LRA) and identify clinical-stage molecules with synergistic LRA activity. Clearance of reactivated cells will be enhanced using a novel strategy for NK cell recruitment and by genetically modifying B cells to produce broadly neutralizing HIV-1 antibodies that enhance reservoir clearance. Finally, gene editing will be deployed for in vivo targeting and elimination of latent provirus not amenable to LRAs.

The outcomes of studies in RF1, RF2, and RF3 will enable the synthesis of a predictive mathematical model to establish the most likely combinations of therapies to achieve an HIV-1 cure, and which will be tested in a capstone aim to establish proof-of-concept for these strategies in NHP models and to enable translation to the clinic.

Scripps Research Institute

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]

La Jolla, California 920371000 United States

Single Zip Code

Martin Delaney Collaboratories for HIV Cure Research (UM1 Clinical Trial Not Allowed) (RFA-AI-20-035)

Amendment Since initial award the total obligations have increased 400% from $5,001,807 to $25,003,080.