Nef stabilizes actin to prevent HIV-1 sensing by RIG-I-like receptors

  • Nat Commun. 2025 Dec 7;16(1):10945. doi: 10.1038/s41467-025-67028-5.
Alexandre Laliberté  #  1 ,  Caterina Prelli Bozzo  #  1  2 ,  Dhiraj Acharya  3 ,  Aurora De Luna  1 ,  Maximilian Hirschenberger  1 ,  Junji Zhu  3 ,  Meta Volcic  1 ,  Bettina Stolp  4 ,  Cristina M Rodriguez-Quinteros  4 ,  Oliver T Fackler  4  5 ,  Michaela U Gack  3 ,  Konstantin M J Sparrer  6  7 ,  Frank Kirchhoff  8
Affiliations
  • 1. Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
  • 2. Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA.
  • 3. Florida Research and Innovation Center, Cleveland Clinic, Port Saint Lucie, USA.
  • 4. Department of Infectious Diseases, Integrative Virology, CIID, Heidelberg University, Medical Faculty Heidelberg, Heidelberg, Germany.
  • 5. German Centre for Infection Research (DZIF), Partner Site Heidelberg, Heidelberg, Germany.
  • 6. Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany. [email protected].
  • 7. German Center for Neurodegenerative Diseases (DZNE), Ulm, Germany. [email protected].
  • 8. Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany. [email protected].
  • # Contributed equally.
PMID: 41354661 DOI: 10.1038/s41467-025-67028-5
Abstract

Sensing of viral pathogens by RIG-I-like receptors (RLRs) requires their priming via dephosphorylation mediated by the protein Phosphatase 1 regulatory subunit 12 C (R12C), which is activated upon virus-induced actin rearrangements. Here, we show that the HIV-1 accessory protein Nef prevents R12C-mediated RLR priming, thereby suppressing viral sensing. HIV-1 variants containing single point mutations in Nef (F/R191A) that ablate its ability to bind the actin-modulating kinase PAK2 trigger increased interferon (IFN) responses in primary CD4+ T cells, macrophages, and dendritic cells. Neutralization of IFN suppresses innate immune activation and enhances the replication of Nef-mutated HIV-1. We further demonstrate that HIV-1 encoding Nef F/R191A is sensed by MDA5 after proviral integration in an R12C-dependent manner. Mechanistically, PAK2 binding by Nef promotes actin repair and stabilization, thereby preventing re-localization of R12C to MDA5 and RIG-I and their subsequent dephosphorylation. Our data identify Nef as an antagonist of actin-R12C-mediated RLR priming, enabling HIV-1 to escape immune control.

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