Evasion of CARD8 Activation During HIV-1 Assembly

As intracellular parasites, viruses must devise sophisticated mechanisms to produce and assemble viral components while suppressing activation of innate immune effectors. Here, we report that coordination of HIV-1 assembly by the viral polyprotein Gag suppresses inappropriately-timed protease (PR) activity to evade the PR activity sensor, CARD8. Employing mutants of Gag, we show that disruption of domains controlling viral assembly site (MA) or virus particle release (NC and p6) lead to premature activation of PR and the CARD8 inflammasome, resulting in IL-1β secretion and pyroptotic cell death. Further, we demonstrate that previously-observed host-adaptive mutations in HIV-1 MA (M30K) and p6 (PTAP duplication) associated with greater fitness in humans differentially modulate the process of viral assembly and budding to evade CARD8-mediated cell death. Altogether, this work reveals adaptation to human CARD8 by HIV-1 Gag upon zoonotic transmission from chimpanzees and suggests that assembly-regulated CARD8 activation influences the trajectory of HIV-1 evolution and fitness in humans.

• Publication year

  2025

• Venue

  bioRxiv

• Publication date

  2025-05-19

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1101/2025.05.19.654850PMID 40475532PMCID 12139941
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• The CARD8 inflammasome dictates HIV/SIV pathogenesis and disease progression.

  2024cited by this paper
• Two-step evolution of HIV-1 budding system leading to pandemic in the human population.

  2024cited by this paper
• The EMBL-EBI Job Dispatcher sequence analysis tools framework in 2024

  2024cited by this paper
• The “basics” of HIV-1 assembly

  2024cited by this paper
• Neutral sphingomyelinase 2 is required for HIV-1 maturation

  2023cited by this paper
• The HIV-1 Viral Protease Is Activated during Assembly and Budding Prior to Particle Release

  2022cited by this paper
• A human-specific motif facilitates CARD8 inflammasome activation after HIV-1 infection

  2022influential reference
• Dynamics of HIV-1 Gag Processing as Revealed by Fluorescence Lifetime Imaging Microscopy and Single Virus Tracking

  2022cited by this paper
• CARD8 is an inflammasome sensor for HIV-1 protease activity

  2021cited by this paper
• Viral manipulation of host cell necroptosis and pyroptosis.

  2021cited by this paper
• Activation of the CARD8 Inflammasome Requires a Disordered Region

  2020cited by this paper
• Maturation of retroviruses.

  2019cited by this paper
• Key Viral Adaptations Preceding the AIDS Pandemic.

  2019cited by this paper
• HIV-1 intron-containing RNA expression induces innate immune activation and T cell dysfunction

  2018cited by this paper
• PTAP motif duplication in the p6 Gag protein confers a replication advantage on HIV-1 subtype C

  2018cited by this paper
• Interferons and HIV Infection: The Good, the Bad, and the Ugly

  2016cited by this paper
• The Race against Protease Activation Defines the Role of ESCRTs in HIV Budding

  2016cited by this paper
• State of the art prediction of HIV-1 protease cleavage sites

  2015cited by this paper
• Elucidation of the Molecular Mechanism Driving Duplication of the HIV-1 PTAP Late Domain

  2015cited by this paper
• HIV-1 assembly, release and maturation

  2015cited by this paper
• Efficient SIVcpz replication in human lymphoid tissue requires viral matrix protein adaptation.

  2012cited by this paper
• HIV Gag-Leucine Zipper Chimeras Form ABCE1-Containing Intermediates and RNase-Resistant Immature Capsids Similar to Those Formed by Wild-Type HIV-1 Gag

  2011cited by this paper
• Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the SAMHD1 protein

  2011cited by this paper
• The Nucleocapsid Region of HIV-1 Gag Cooperates with the PTAP and LYPXnL Late Domains to Recruit the Cellular Machinery Necessary for Viral Budding

  2009cited by this paper
• Analysis of human immunodeficiency virus matrix domain replacements.

  2008cited by this paper
• Intracellular HIV-1 Gag localization is impaired by mutations in the nucleocapsid zinc fingers

  2007cited by this paper
• Adaptation of HIV-1 to its human host.

  2007cited by this paper
• Generation of Infectious Molecular Clones of Simian Immunodeficiency Virus from Fecal Consensus Sequences of Wild Chimpanzees

  2007cited by this paper
• Human Immunodeficiency Virus Type 1 Gag Engages the Bro1 Domain of ALIX/AIP1 through the Nucleocapsid

  2007cited by this paper
• Structural basis for targeting HIV-1 Gag proteins to the plasma membrane for virus assembly.

  2006cited by this paper
• Potent Nonnucleoside Reverse Transcriptase Inhibitors Target HIV-1 Gag-Pol

  2006cited by this paper
• Cell-Type-Dependent Targeting of Human Immunodeficiency Virus Type 1 Assembly to the Plasma Membrane and the Multivesicular Body

  2004cited by this paper
• Phosphatidylinositol (4,5) bisphosphate regulates HIV-1 Gag targeting to the plasma membrane.

  2004cited by this paper
• Entropic switch regulates myristate exposure in the HIV-1 matrix protein.

  2004cited by this paper
• Elimination of Protease Activity Restores Efficient Virion Production to a Human Immunodeficiency Virus Type 1 Nucleocapsid Deletion Mutant

  2003cited by this paper
• Substrate shape determines specificity of recognition for HIV-1 protease: analysis of crystal structures of six substrate complexes.

  2002cited by this paper
• Plasma membrane rafts play a critical role in HIV-1 assembly and release

  2001cited by this paper
• Efficient HIV‐1 replication can occur in the absence of the viral matrix protein

  1998cited by this paper
• Mutations of the Human Immunodeficiency Virus Type 1 p6Gag Domain Result in Reduced Retention of Pol Proteins during Virus Assembly

  1998cited by this paper
• HIV‐1 infection of non‐dividing cells: evidence that the amino‐terminal basic region of the viral matrix protein is important for Gag processing but not for post‐entry nuclear import

  1997cited by this paper
• p6Gag is required for particle production from full-length human immunodeficiency virus type 1 molecular clones expressing protease

  1995cited by this paper

• No citing papers are available for this paper.