2. Academic Validation
  3. Nef stabilizes actin to prevent HIV-1 sensing by RIG-I-like receptors

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

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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