R01AI167644

Role of RHCMV in Shaping the SIV Proviral Landscape - Project Summary/Abstract

The main obstacle to curing HIV-1 infection is a reservoir that consists of resting memory CD4 T cells whose genomes contain inducible and replication-competent HIV-1 proviruses. Decay of the reservoir is slow and requires lifelong antiretroviral therapy (ART). It has become increasingly clear that the predominant mechanism sustaining HIV-1 persistence during ART is the physiologic proliferation of latent-infected memory CD4 T cells. Infected CD4 T cells can proliferate without producing virus, resulting in daughter cells harboring expanded HIV-1 proviral clones that share identical sequence and host integration sites. However, the rate of expansion among distinct proviral clones in this setting is not equal. In some individuals, upwards of 30% of proviruses sampled can belong to populations that are highly clonally expanded, a mechanism consistent with clonal proliferation by antigen encounter. Establishing a link between particular antigens and the degree to which they independently contribute to HIV persistence, however, is an unresolved question.

Cytomegalovirus (CMV) is a latent betaherpesvirus that, while asymptomatic in immunocompetent hosts, persistently stimulates the memory T cell pool. Persons living with HIV are near universally coinfected with CMV. In this project, we have assembled a multidisciplinary team of investigators to directly assess the degree to which chronic antigenic stimulation by CMV (i) promotes proliferation of the memory CD4 T cell pool, (ii) contributes to clonal diversity and size of the HIV-1 reservoir during ART, and (iii) impacts the time to viral recrudescence when ART is interrupted. Specifically, we will utilize the well-established model of ART-treated SIV-infected rhesus macaques to examine these questions by a dual approach. The first will exploit the availability of pathogen-free, rhesus CMV (RHCMV)-naïve rhesus macaques (RMs) to compare SIV reservoir dynamics in the presence or absence of CMV. The second will assess measures of SIV persistence when CMV replication is blocked pharmacologically with antiviral cidofovir.

Critical to our aims are that we will interrogate SIV proviral DNA at multiple longitudinal timepoints, in multiple tissues, and with several assays that inform both quantitative and qualitative aspects of the SIV reservoir. We believe that the comprehensive, highly synergistic, and rigorously controlled studies we propose will (i) identify an immunodominant target that promotes turnover of memory CD4 T cells during ART and, by extension, persistence of the HIV-1 reservoir, and (ii) provide a rationale to employ recent well-tolerated FDA-approved CMV antivirals as a means to accelerate HIV-1 clearance.

The Administrators Of Tulane Educational Fund

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]

Covington, Louisiana 704338915 United States

Single Zip Code

Stephen I. Katz Early Stage Investigator Research Project Grant (R01 Clinical Trial Not Allowed) (PAR-21-038)

Amendment Since initial award the total obligations have increased 310% from $850,728 to $3,487,832.