P01AI178376

Multi-omics identification and validation of mechanisms triggered by immune interventions aimed at reducing the size of the replication competent reservoir - in spite of antiretroviral (ART) drugs which effectively control plasma viremia, a pool of HIV latently infected cells form a persistent reservoir that prevents clearance of virally infected cells.

Upon cessation of ART treatment, this reservoir leads to a rapid rebound in plasma viremia, even if ART is initiated early during acute infection. Eradicating or permanently silencing this reservoir is the focus of many HIV cure strategies.

Immune dysfunction including impaired T cell responses are a hallmark of HIV disease. Immune directed cure strategies seek to overcome this dysregulation to restore normal immune function and promote killing of HIV infected cells.

The limited clinical efficacy of immune-based cure strategies to date suggests that there may be more to restoring immune function than targeting T and B cells. We hypothesize that cure strategies which activate and restore normal innate and adaptive immune function will more effectively reduce the HIV reservoir and limit viral rebound after cessation of ART.

To test this hypothesis, we will employ an expansive multi-omic platform consisting of virological, immunological, and molecular assays to define the role of simultaneous re-invigoration of the innate and adaptive immune systems by 3 distinct cure strategies on HIV reservoir dynamics and viral rebound after discontinuing ART.

The first strategy (Project 1) will investigate how co-treatment with Lefitolimod (innate immune TLR9 agonist) and broadly neutralizing antibodies promotes clearance of the HIV reservoir by priming innate immune responses and providing the antibodies to target infected cells using Fc-mediated innate immune effector functions.

The second strategy (Project 2) will test how blockade of the PD-1/PD-L1 signaling axis by monoclonal antibody therapy leads to enhanced inflammatory monocyte/macrophage responses and restored CD4 and CD8 T cell function.

The third strategy (Project 3) will study how engraftment with allogeneic hematopoietic stem cells expressing the CCR5D32 mutation or autologous infusion of CCR5 deleted CD4+ T cells repopulate the immune compartment with functional effector cells that are refractory to HIV infection leading to killing of the HIV reservoir and a lack of viral rebound.

For all projects, we will define how differences in the host environment resulting from host and microbial metabolites modulate the immunological mechanisms identified to mediate clearance of the HIV reservoir and/or limit viral rebound.

Analysis of results will be performed by a dedicated machine learning and modeling core. This core will ultimately be responsible for generating integrated multi-omic network models which predict the microbiome/metabolite features which directly regulate the immune mechanisms associated with reduction in either the HIV reservoir or viral rebound; both within each cohort/project and across projects to identify common features to multiple strategies.

Our team of experts have collaborated extensively and are uniquely positioned to complete the goals of this program.

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.

93.855 - Allergy and Infectious Diseases Research

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

Atlanta, Georgia 303221119 United States

Single Zip Code

A Multi-omics Approach to Immune Responses in HIV Vaccination and Intervention (P01 Clinical Trial Not Allowed) (RFA-AI-22-038)

Amendment Since initial award the total obligations have increased 189% from $1,293,876 to $3,741,426.