P01AI178375

Multi-Omic Understanding of the Transformed Host T-Cell Response to HIV Following Therapeutic Vaccination

Therapeutic HIV vaccines confront an immune system whose anti-pathogen responses are established and have usually been evolving for years. T-cell responses to immunodominant epitopes have been generated and may have been maintained—or could have forced viral escape and eventual expansion of T cells with alternative, originally sub-dominant specificities.

Many HIV-specific T cells have low proliferative capacity, rendering them incapable of a robust response when antiretroviral treatment is stopped. Furthermore, the established T-cell repertoire failed to control acute infection, so expansion of pre-existing T cells with their attendant functional deficiencies is unlikely to be therapeutically effective. The primary goal of therapeutic vaccination must instead be expansion of new T-cell clones with superior function, and/or the restoration of function to pre-existing memory cells. We suggest that only such qualitative improvements can provide the host with new capacity for control over the virus.

A central objective of our program is to understand the extent to which pre-existing host immune and metabolic features constrain the quality of T-cell responses to therapeutic vaccination. Which immunometabolic conditions predict and perhaps foster qualitatively superior responses? What fraction of the T-cell response to vaccination is represented by new and previously undetected clonotypes, and how do the functional capacities and differentiation of the new clonotypes differ from pre-existing ones?

A second major objective is to evaluate the relative ability of different vaccine regimens and metabolic interventions to expand new HIV/SIV-specific T cells with stem-like qualities. We and others have shown that HIV-specific T cells in natural HIV controllers express high levels of the memory-promoting transcription factor, TCF-1, retain proliferative capacity, and exhibit metabolic plasticity. We hypothesize that vaccine-induced cells with stem-like properties often derive from naïve T-cell clonotypes not previously expanded or chronically exposed to antigen, and that different vaccine regimens differ in their ability to recruit such cells.

A third and central objective of our effort is to learn how peptide specificity, stemness, and metabolic capacities of T cells responding to vaccination are related to control over viremia during ATI. A large literature supports our premise that high T-cell quality is required for control over viremia, and more specifically that T cell memory, or "stemness", features are associated with effective host responses. However, these connections remain relatively unexplored in the context of therapeutic vaccination, in part due to scarcity of large therapeutic-vaccine studies that have yielded an appreciable efficacy signal. We will use samples from human and non-human primate therapeutic-vaccine studies that have shown evidence for T cell-mediated virologic suppression to understand if the T-cell features previously linked to control over infection are also typical of successful immune responses to therapeutic vaccines.

Davis 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.

93.855 - Allergy and Infectious Diseases Research

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

Davis, California 95616 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 End Date has been shortened from 05/31/28 to 04/30/28 and the total obligations have increased 259% from $1,494,209 to $5,370,395.