R01AI155680

Cytomegalovirus (CMV), the Gut Barrier, and Immune Dysfunction in HIV - Abstract

This revised collaborative R01 application addresses the impact of cytomegalovirus (CMV) on the gastrointestinal mucosa in chronic HIV infection. We hypothesize that CMV infection contributes to intestinal barrier dysfunction and consequent immune activation that persist in chronic HIV infection despite suppressive antiretroviral therapy (ART).

In Aim 1, based on strong preliminary studies, we hypothesize that CMV persistence in the gastrointestinal tract results in part from the failure of CMV-specific CD8+ T-cells to localize to this tissue. To determine the breadth and functionality of CMV-specific T-cell responses in the gut, we will measure responses in colorectal tissue from participants in the SCOPE cohort at UCSF. To determine the effects of CMV infection on antigen presentation in the gut, we will employ the rhesus macaque model of CMV (RHCMV) and SIVMAC to study interactions between mucosal dendritic cells (DC) and T-cells ex vivo.

In Aim 2, we will leverage an externally-funded clinical trial (AIDS Clinical Trials Group Study #A5383) to directly test the hypothesis that asymptomatic CMV replication contributes significantly to microbial translocation in treated HIV disease. We will determine the effects of suppression of CMV replication with letermovir on systemic biomarkers of microbial translocation as well as immune activation and gut barrier integrity assessed directly in gut mucosal tissues.

Taken together, these studies will determine the contributions of CMV to immune activation in HIV disease, and the mechanistic bases for these effects. Aim 3 leverages a second ACTG study (#A5355) to determine whether a modified vaccine Ankara (MVA)-based CMV vaccine can increase systemic and/or gut-homing and mucosal CMV-specific T-cell responses in treated HIV infection. Failure of a therapeutic anti-CMV vaccine to elicit gut-homing CMV-specific T-cell responses and to reduce mucosal CMV shedding may compromise its ability to reduce systemic immune activation in treated HIV infection and would highlight the need for optimization of vaccination strategies to improve mucosal responses. (Note: Aims 2 and 3 do not meet the NIH definition of a clinical trial; the ancillary studies in these aims only add additional measures to pre-existing trials).

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

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

Amendment Since initial award the total obligations have increased 428% from $772,678 to $4,077,185.