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

Author

Listed:
  • Alexandre Laliberté

    (Ulm University Medical Center, Institute of Molecular Virology)

  • Caterina Prelli Bozzo

    (Ulm University Medical Center, Institute of Molecular Virology
    Yale University School of Medicine, Department of Microbial Pathogenesis)

  • Dhiraj Acharya

    (Cleveland Clinic, Florida Research and Innovation Center)

  • Aurora De Luna

    (Ulm University Medical Center, Institute of Molecular Virology)

  • Maximilian Hirschenberger

    (Ulm University Medical Center, Institute of Molecular Virology)

  • Junji Zhu

    (Cleveland Clinic, Florida Research and Innovation Center)

  • Meta Volcic

    (Ulm University Medical Center, Institute of Molecular Virology)

  • Bettina Stolp

    (Medical Faculty Heidelberg, Department of Infectious Diseases, Integrative Virology, CIID, Heidelberg University)

  • Cristina M. Rodriguez-Quinteros

    (Medical Faculty Heidelberg, Department of Infectious Diseases, Integrative Virology, CIID, Heidelberg University)

  • Oliver T. Fackler

    (Medical Faculty Heidelberg, Department of Infectious Diseases, Integrative Virology, CIID, Heidelberg University
    Partner Site Heidelberg, German Centre for Infection Research (DZIF))

  • Michaela U. Gack

    (Cleveland Clinic, Florida Research and Innovation Center)

  • Konstantin M. J. Sparrer

    (Ulm University Medical Center, Institute of Molecular Virology
    German Center for Neurodegenerative Diseases (DZNE))

  • Frank Kirchhoff

    (Ulm University Medical Center, Institute of Molecular Virology)

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.

Suggested Citation

  • Alexandre Laliberté & Caterina Prelli Bozzo & Dhiraj Acharya & Aurora De Luna & Maximilian Hirschenberger & Junji Zhu & Meta Volcic & Bettina Stolp & Cristina M. Rodriguez-Quinteros & Oliver T. Fackle, 2025. "Nef stabilizes actin to prevent HIV-1 sensing by RIG-I-like receptors," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-67028-5
    DOI: 10.1038/s41467-025-67028-5
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