P01AI169606

The Heterogeneous HIV Expressing Reservoir: Dynamics, Persistence Mechanisms, Tissue Distribution, and Contribution to Rebound - Abstract:

While the latent and intact HIV reservoirs pose theoretical barriers to cure, it is also critical to understand those cells that are reactivated and/or express HIV in vivo, which contribute to immune activation and may have more potential to initiate rebound after ART interruption.

However, prior studies of the "transcriptionally active reservoir" have not been able to fully characterize the heterogeneity of these cells, which vary in terms of whether they transcribe incomplete or completed and spliced HIV RNA, whether the HIV RNA is transcribed from defective or intact proviruses, and whether it is translated into HIV protein.

This P01 focuses on the novel hypothesis that subsets of cells expressing different types of HIV RNA and/or protein will differ in terms of their frequency, survival or clearance rate, contribution to immune activation, cellular gene expression, differences across tissues, rebound potential, and susceptibility to new therapies aimed at HIV cure.

To test these hypotheses, the three synergistic projects in this P01 will employ an array of new and cutting-edge technologies that can distinguish HIV-expressing cells based on the processivity of the HIV RNA, presence or absence of deletions or hypermutations, translation into HIV protein, and human transcriptome/proteome.

Project #1 will measure the changes in blocks to HIV transcription and levels of defective or intact HIV RNA and protein over time in the blood of elite controllers and individuals who initiate ART during acute or chronic infection (Aim 1), determine how they relate to immune responses and immune activation/inflammation (Aim 2), and determine how differential expression of host cell genes relates to the ability of these cells to express HIV and survive in blood and lymph nodes (Aim 3).

In Project #2, we will measure the total burden of intact/defective proviruses and intact/defective HIV RNA across the full spectrum of different organs and tissues in vivo (Aim 1), define the frequencies and phenotypes of cells expressing different types of HIV RNA transcripts across tissues (Aim 2), and determine the in situ impact of HIV burden and residual transcriptional activity on host cell factors in tissue-resident lymphoid and myeloid cells (Aim 3).

Project #3 will determine which reservoirs of HIV-expressing cells (as well as the intact and inducible reservoir) and host factors best predict the timing of rebound in individuals who initiated ART during acute vs. chronic infection (Aim 1), define the features of the rebounding virus and earliest detectable infected cells during treatment interruption (Aim 2), and assess the effects of immune-based cure interventions on these HIV reservoirs (Aim 3).

To achieve these goals, the Bioinformatics Core will help analyze transcriptomic, proteomic, and high-dimensional data, while the Administrative Core will facilitate scientific crosstalk and collaboration, coordinate allocation of resources, and track and evaluate progress.

Findings from these studies will generate a wealth of new knowledge about the HIV-infected cells that contribute to immune activation on ART and virologic rebound after ART interruption, which may lead to new approaches aimed at HIV cure or reducing HIV-associated immune activation and organ damage.

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 941211563 United States

Single Zip Code

Understanding HIV Reservoir Dynamics (P01, Clinical Trial Not Allowed) (RFA-AI-21-013)

Amendment Since initial award the total obligations have increased 295% from $1,578,386 to $6,228,573.