UM1AI164562

Enterprise for Research and Advocacy to Stop and Eradicate HIV (ERASE-HIV) - Abstract

The presence of a reservoir of cells harboring integrated, replication-competent virus that persists under long-term, fully suppressive antiretroviral therapy (ART) and the inability of the host immune responses to control the initial events of viral replication that follow ART interruption are critical barriers to curing HIV infection. Thus, novel therapeutic strategies to remove these barriers are critically needed.

The overarching hypotheses of ERASE HIV are: (I) decreased and/or dysfunctional CD8+ T and NK cell antiviral functions, combined with the recently-described CD8+ T-cell-mediated transcriptional silencing of HIV, favor HIV persistence under ART and prevent the control of viremia if ART is stopped; and (II) novel approaches to elicit effective CD8+ T-cell, NK cell, and antibody-dependent cellular cytotoxicity (ADCC) functions while inhibiting the CD8+ T-cell-mediated virus silencing will promote remission and/or eradication of HIV.

The overarching goal of ERASE HIV is to identify novel mechanisms of HIV persistence and to test them in the most relevant pre-clinical animal models through mechanistically-oriented, community-supported therapeutic strategies that can be ultimately translated to cure HIV infection in humans.

ERASE HIV includes three highly integrated research foci (RFs). RF1 is aimed at identifying the molecular and cellular mechanisms underlying the two distinct antiviral activities of CD8+ T-cells: the MHC-restricted, antigen-specific response that directly eliminates virus-infected cells, and the non-MHC restricted, non-cytolytic silencing of HIV transcription. As such, RF1 will provide the conceptual basis for the interventions tested in RF2 and RF3.

RF2 will use animal models of ART-treated HIV infection to (I) restore CD8+ T and NK cell function with a combined a-IL-10 and IL-15 superagonist (N-803) strategy; (II) target rebounding virus by using a CD4-mimetic compound (CD4MC) to enhance antibody recognition of cells expressing HIV Env and their elimination via ADCC; and (III) determine if improving CD8+ T and NK cell function via a-IL-10 and N-803 synergizes with CD4MC to clear infected cells.

RF3 will determine if suppression of the latency-promoting activity of CD8+ T-cells, coupled with N-803 and interventions to promote apoptosis (BCL-2 inhibitors) or immune-mediated removal (CD4MC) of cells that have reactivated virus, will reduce the reservoir size.

In all, we will exploit the synergy between the mechanistic data generated in RF1 and the in vivo interventions in RF2 and RF3 to validate a strategy that targets both HIV persistence during ART and HIV recrudescence after ART interruption.

ERASE HIV is supported by experts in HIV advocacy (SisterLove); recognition and killing of HIV Env-expressing cells (Finzi/Sodroski); T and NK cell biology (Sekaly/Ribeiro/Deleage/Parsons); reservoir assays and latency models (Kulpa/Jones/Litchterfeld/Howell); pre-clinical animal studies (Paiardini/Silvestri/Garcia/Saez-Cirion/Keele/Kumar); mathematical modeling (Davenport); and therapeutics development (Merck and ImmunityBio) for HIV cure.

We believe that the proposed mechanistically-oriented pre-clinical work will inform strategies that can be translated in clinical trials to achieve prolonged viral remission in people with HIV.

Emory 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.

93.279 - Drug Abuse and Addiction Research Programs

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

National Institute on Drug Abuse (NIDA) [HHS - NIH]

Atlanta, Georgia 303294208 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 20168% from $125,000 to $25,334,968.