R37AI155171

Elite controllers as a model for a cure of HIV-1 infection - Abstract

While a sterilizing cure of HIV-1 infection has been reported in two individuals after a stem cell transplant with CCR532 homozygous cells, a spontaneous functional cure of HIV-1 occurs in 0.3-0.5% of all infected individuals. These individuals, termed elite controllers (EC), maintain undetectable levels of HIV-1 replication in the absence of treatment, despite the repeated isolation of replication-competent virus from viral reservoir cells.

These individuals provide living evidence that spontaneous control of HIV-1 infection is possible, and the identification of virological and immunological mechanisms underlying such a remarkable disease outcome holds promise for inducing a functional cure of HIV-1 infection in broader HIV-1 patient populations.

Here, we propose the novel hypothesis that undetectable viral loads in EC are related to specific genetic and epigenetic features of proviral HIV-1 DNA in reservoir cells. Based on strong preliminary data, we posit that intact HIV-1 proviruses from EC are preferentially located in non-genic chromosomal regions that do not permit effective viral gene transcription, resulting in a proviral landscape in deep latency and with very limited responsiveness to reactivation stimuli in vivo.

In addition, we propose that intact proviruses from EC are also frequently integrated into chromosomal regions that show epigenetic characteristics of repressive chromatin, evidenced by enhanced distance to accessible chromatin and enrichment with inhibitory histone marks and hypermethylated DNA.

To investigate this, we plan to longitudinally analyze the frequency and chromosomal location of intact proviruses in blood and lymphoid tissues of EC, using novel experimental and biocomputational analysis approaches (Specific Aim 1). In addition, we will conduct a detailed analysis of epigenetic chromatin features at the integration sites of intact proviruses, using next-generation sequencing assays for genome-wide characterization of chromatin accessibility, RNA transcription, activating and inhibitory histone marks, and DNA methylation (Specific Aim 2).

Finally, we will perform functional experiments to evaluate responsiveness to viral reactivation stimuli, using novel single-cell assays to simultaneously characterize proviral sequence, chromosomal integration sites, and HIV-1 transcriptional activity of single viral reservoir cells (Specific Aim 3). These highly innovative single-reservoir-cell assays will allow us to functionally test the hypothesis that chromosomal locations of intact proviruses in EC maintain a state of deep latency and confer resistance to viral reactivation stimuli.

If successful, this project will significantly expand our current understanding of how natural, drug-free control is possible and be highly informative for inducing natural control in broader patient populations.

The General Hospital Corporation

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]

Cambridge, Massachusetts 021393526 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-19-056)

Amendment Since initial award the End Date has been extended from 08/31/25 to 08/31/26 and the total obligations have increased 299% from $867,590 to $3,458,462.