R01AI170239

Targeting HIV-Specific T Cell Differentiation Programs to Enhance Post-Treatment Control of HIV - Project Summary

Nearly 40 million people worldwide are infected with HIV, an infection for which there is no cure. Many strategies that aim to cure HIV focus on harnessing HIV-specific T cells to control the virus that rebounds after antiretroviral therapy (ART) is discontinued because of their ability to specifically recognize and kill HIV-infected cells. However, HIV-specific T cell therapies will not be effective if they cannot overcome the T cell exhaustion that occurs in the setting of chronic antigen stimulation.

In mouse models of chronic infection and cancer, T cells enriched for a stem cell memory (TSCM) phenotype or stem-like transcriptional program robustly expand and differentiate into effector cells while resisting exhaustion. We have found that the expression of the stem/memory-promoting transcription factor, TCF-1, is associated with high in vitro proliferative capacity in HIV-specific CD8+ T cells in individuals who naturally control HIV infection and that TCF-1 overexpression leads to better HIV-specific T cell expansion after in vitro peptide stimulation.

While T cells that are enriched for stemness programs proliferate and control cancer better in animal models, it is currently unknown whether stem-like T cells (versus, for example, effector-differentiated T cells) are optimal for controlling HIV after ART is stopped. The overarching goal of this proposal is to directly establish the role of T cell stemness in promoting the ability of HIV-specific T cells to expand a functional effector population to control HIV infection after discontinuation of ART.

In Aim 1, we will use multi-modal high-dimensional single cell phenotypic and transcriptional profiling to establish whether the proportion of stem-like virus-specific CD8+ T cells on ART correlates with their in vivo expansion and subsequent control of HIV in humans or SIV in macaques after treatment interruption.

In Aim 2, we will use envelope (Env)-targeting HIV-specific CAR-T cells with potent anti-HIV activity (DuCAR-T cells) as a model to ask how precisely tuning the level of stemness influences the ability of CAR-T cells to suppress HIV long-term in the HIV participant-derived xenograft (PDX) mouse model.

In Aim 3, we will leverage blood and tissue samples from a highly unique clinical trial of people with HIV on ART who receive an infusion of anti-HIV DuCAR-T cells and undergo an Analytical Treatment Interruption (ATI). We hypothesize that CAR-T cells that are more stem-like prior to infusion (i.e., either the CAR-T cells in the total pre-infusion product or sub-populations that we identify pre-infusion and then track in vivo post-infusion using single cell paired alpha/beta T cell receptor sequences as "barcodes") will expand a larger, less-exhausted effector population.

These studies will test for the first time in the context of HIV infection the compelling hypothesis that T cells enriched for stemness have greater proliferative capacity and durability and are able to give rise to effector T cells that are better able to control HIV in vivo. We will also comprehensively evaluate other T cell differentiation states that might associate with HIV control after ART discontinuation.

Completion of these studies will result in new knowledge about the role of HIV-specific T cell differentiation states in the development of effective T cell-based strategies for HIV cure.

San Francisco Regents Of The 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]

San Francisco, California 941432500 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 307% from $791,450 to $3,224,130.