CARD8 is an inflammasome sensor for HIV-1 protease activity

  • Science. 2021 Mar 19;371(6535):eabe1707. doi: 10.1126/science.abe1707.
Qiankun Wang  1 ,  Hongbo Gao  1 ,  Kolin M Clark  1 ,  Christian Shema Mugisha  2 ,  Keanu Davis  2 ,  Jack P Tang  3 ,  Gray H Harlan  1 ,  Carl J DeSelm  3  4 ,  Rachel M Presti  1 ,  Sebla B Kutluay  2 ,  Liang Shan  5  4
Affiliations
  • 1. Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA.
  • 2. Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO, USA.
  • 3. Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO, USA.
  • 4. Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, Saint Louis, MO, USA.
  • 5. Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA. [email protected].
PMID: 33542150 DOI: 10.1126/science.abe1707
Abstract

HIV-1 has high mutation rates and exists as mutant swarms within the host. Rapid evolution of HIV-1 allows the virus to outpace the host immune system, leading to viral persistence. Approaches to targeting immutable components are needed to clear HIV-1 Infection. Here, we report that the Caspase recruitment domain-containing protein 8 (CARD8) inflammasome senses HIV-1 protease activity. HIV-1 can evade CARD8 sensing because its protease remains inactive in infected cells before viral budding. Premature intracellular activation of the viral protease triggered CARD8 inflammasome-mediated Pyroptosis of HIV-1-infected cells. This strategy led to the clearance of latent HIV-1 in patient CD4+ T cells after viral reactivation. Thus, our study identifies CARD8 as an inflammasome sensor of HIV-1, which holds promise as a strategy for the clearance of persistent HIV-1 Infection.