# Understand the role of CARD8 inflammasome in HIV-1 infection

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $701,978

## Abstract

Abstract
Despite antiretroviral therapy (ART), HIV-1 infection is not curable due to the presence of viral
latent reservoirs primarily in long-lived resting memory CD4+ T cells. The viral latent reservoirs
are the major barrier to HIV-1 eradication. The “shock and kill” strategy for HIV-1 eradication
involves the use of latency-reversing agents (LRAs) to induce viral gene expression, which
renders the infected cells susceptible to viral cytopathic effects or immune clearance. However,
in ART-treated patients, the latent HIV-1 resides in cells is resistant to viral- or immune-mediated
apoptotic cell death and often carries mutations to escape recognition by T cells or antibodies.
Therefore, novel approaches to target immutable components of the virus such as essential viral
protein functions are needed. Inflammasome is a critical molecular complex that mediates
inflammation and pyroptotic cell death in response to microbial or danger signals. In humans, the
physiologic ligand(s) for the CARD8 inflammasome remains unknown. Our studies demonstrate
that HIV-1 protease degrades the CARD8 N-terminal domain and releases the C-terminus for
inflammasome activation. In HIV-1-infected cells, the viral protease remains inactive as a subunit
of viral Gag-Pol polyprotein. After virus budding, it is activated through Gag-Pol dimerization. We
show that premature activation of intracellular HIV-1 protease by non-nucleoside reverse
transcriptase inhibitors (NNRTI) triggers CARD8 sensing and killing of HIV-infected macrophages
and CD4+ T cells. All subtypes of HIV-1 can be sensed by CARD8 despite substantial viral
diversity. Our finding suggests that targeted activation of CARD8 inflammasome is a promising
strategy to eliminate latent HIV-1 reservoirs. In this proposed study, we will: 1) perform ex vivo
assessment and optimization of the CARD8-based “shock and kill strategy” for clearing latent
HIV-1 in patient CD4+ T cells; 2) understand the molecular mechanisms of HIV-1 protease-
mediated CARD8 inflammasome activation; 3) test CARD8-based “shock and kill” strategy in
humanized mouse model of HIV-1 latency. Our proposed study will advance the understanding
of the physiological mechanisms of CARD8 inflammasome activation and its role in HIV-1
infection, which will provide critical implications to HIV cure research.

## Key facts

- **NIH application ID:** 10829426
- **Project number:** 5R01AI162203-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** LIANG SHAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $701,978
- **Award type:** 5
- **Project period:** 2021-05-21 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10829426

## Citation

> US National Institutes of Health, RePORTER application 10829426, Understand the role of CARD8 inflammasome in HIV-1 infection (5R01AI162203-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10829426. Licensed CC0.

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