# Harnessing the CARD8 Inflammasome for HIV Reservoir Elimination > **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $797,024 ## Abstract 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... ## Key facts - **NIH application ID:** 10807027 - **Project number:** 5R01AI176594-02 - **Recipient organization:** WASHINGTON UNIVERSITY - **Principal Investigator:** LIANG SHAN - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $797,024 - **Award type:** 5 - **Project period:** 2023-03-10 → 2028-02-29 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10807027 ## Citation > US National Institutes of Health, RePORTER application 10807027, Harnessing the CARD8 Inflammasome for HIV Reservoir Elimination (5R01AI176594-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10807027. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*