R01AI177327

Exploration of novel block-and-lock agents alone and in combination for HIV remission in humanized mice - Abstract

HIV-1 transcriptional inhibitors have immense potential in functional cure approaches and could transform the way we treat HIV infections. Unlike current antiretroviral therapy (ART), transcriptional inhibitors offer the prospect of reducing residual viremia derived from reservoir of long-lived cells containing integrated proviruses, likely reducing ongoing the chronic immune activation, inflammation and HIV-associated co-morbidities still experienced by ART-adherent individuals living with HIV.

Furthermore, we believe transcriptional inhibitors are amenable to block-and-lock functional cure approaches, aimed at the durable suppression of HIV in the absence of daily therapy, through permanent epigenetic silencing of integrated proviruses. This hypothesis was founded on the activity of the potent Tat inhibitor didehydro-cortistatin A (DCA). In in vitro and in vivo models of HIV latency, DCA inhibition of HIV transcription over time prompts the viral promoter into deep transcriptional inhibition, limiting viral reactivation upon treatment interruption or with latency reactivating agents (LRAs).

Despite their great potential, there are still no HIV transcriptional inhibitors in the clinic, and challenges with the cost of large-scale production of DCA are slowing its progression towards clinical studies.

Here we propose to investigate the repurposing the FDA approved aldosterone antagonist spironolactone (SP) for HIV transcriptional inhibition. An off-target activity of SP is the degradation of the XPB subunit of the general transcription factor TFIIH, a key player in RNAPII initiation at the transcriptional start site (TSS) of genes. We demonstrated in vitro that SP treatment or shRNA knockdown of XPB selectively inhibits HIV transcription and blocks viral reactivation from latency without global transcriptomic defects. This study highlighted the host factor XPB as a novel drug target and SP as a potential block-and-lock agent.

Here we propose to explore the potential of SP, alone or in combination with DCA, as a block-and-lock agent in the humanized bone-marrow, thymus liver (BLT) mouse model of HIV infection by:

1) Determine the relationship between SP treatment length with residual viremia levels in tissues and correlates of chronic immune activation/inflammation in HIV infected ART-suppressed BLT mice.

2) Assess the ability of SP to maintain deep latency as a single drug in the absence of ART and study viral resistance evolution.

3) Impact of DCA and SP in combination as front-line therapy on the size of the established viral reservoir and time to viral rebound.

We predict that longer treatment lengths of HIV infected BLT mice with SP will correlate with improved reduction of low-grade HIV persistent transcription from the viral reservoir and likely chronic immune activation. Importantly, we seek to demonstrate that once deep transcriptional suppression is established, SP alone blocks viral rebound. In addition, when used as front-line therapy we expect a reduction in the size of the established viral reservoir and the combination with DCA will improve the outcome.

This study will provide an important proof-of-concept for the use of transcriptional inhibitors to treat people living with HIV and explore optimal experimental settings to be tested in future clinical trials.

University Of Florida

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]

Jupiter, Florida 33458 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 93% from $1,806,314 to $3,489,695.