R01AI176594

Harnessing the CARD8 inflammasome for HIV reservoir elimination - Project Summary

The HIV-1 reservoir is a stable pool of latently infected CD4+ T cells that rekindles viral replication even after decades of antiretroviral therapy (ART). ART alone is not curative, requiring life-long treatment for people living with HIV-1 (PLWH).

The main strategies attempted so far to eliminate HIV-1-infected cells face multiple challenges, including the selection of escape variants, resistance to apoptosis, T cell exhaustion, downregulation of MHC-I by HIV-1, and localization of infected cells in immune sanctuaries.

This research program has the long-term goal of developing new therapeutic approaches to eliminate or control the HIV reservoir, leading to a drug-free remission.

We recently discovered that the inflammasome protein CARD8 senses the enzymatic activity of the HIV-1 protease. We demonstrated that non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as efavirenz (EFV) promote dimerization of Gag-Pol and cause premature intracellular activation of protease. HIV-1 protease cleaves CARD8, driving the formation of caspase-1-dependent inflammasome and pyroptosis.

All clinical HIV-1 isolates can be sensed by CARD8 despite viral diversity because it recognizes essential protease functions.

The overall objective of this application is to harness CARD8 inflammasome to develop a novel approach to enhance HIV-1 reservoir elimination independently of CTLs or antibodies and trigger cell killing through non-apoptotic cell death.

The underlying central hypothesis is that EFV-induced activation of CARD8, in combination with CARD8-enhancing drugs, can clear cells with transcriptionally active proviruses, reduce viral reservoir expansion, and gradually remove proviruses integrated into euchromatin regions.

The rationale for the project is that enhancing the negative selection forces will reshape the proviral landscape, accelerate its decay, and reduce viral reactivation.

The central hypothesis will be tested by pursuing three specific aims:

1) Establish EFV-induced CARD8 activation and killing of expanding HIV reservoir cells upon stimulation with cognate antigens ex vivo;
2) Determine the impact of EFV on HIV-1 reservoirs in humanized mice; and
3) Investigate the impact of EFV on HIV-1 reservoirs in PLWH in vivo by studying banked samples from clinical trials.

The research proposed in this application is innovative because, compared to the status quo, it focuses on a new mechanism independent from HIV-1 diversity and cell susceptibility to apoptosis.

The proposed research is significant because it is expected to provide the groundwork for the development of a new curative strategy that is scalable, broadly applicable in different contexts of clinical research, and can be easily combined with other interventions aiming to achieve HIV-1 remission.

At completion, the proposed work will inform future pre-clinical and clinical research on the development of new antiretroviral compounds that can potently eliminate HIV-1-infected cells by activating CARD8-sensing of HIV-1 protease activity.

Washington University

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]

Saint Louis, Missouri 631101010 United States

Single Zip Code

Enhancing HIV Reservoir Susceptibility to Elimination (R01 Clinical Trial Not Allowed) (RFA-AI-22-025)

Amendment Since initial award the total obligations have increased 97% from $1,624,284 to $3,203,214.