%0 Journal Article
%A Laliberté, Alexandre
%A Prelli Bozzo, Caterina
%A Acharya, Dhiraj
%A De Luna, Aurora
%A Hirschenberger, Maximilian
%A Zhu, Junji
%A Volcic, Meta
%A Stolp, Bettina
%A Rodriguez-Quinteros, Cristina M
%A Fackler, Oliver T
%A Gack, Michaela U
%A Sparrer, Konstantin M J
%A Kirchhoff, Frank
%T Nef stabilizes actin to prevent HIV-1 sensing by RIG-I-like receptors.
%J Nature Communications
%V 16
%N 1
%@ 2041-1723
%C [London]
%I Springer Nature
%M DZNE-2025-01353
%P 10945
%D 2025
%X 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.
%K Humans
%K HIV-1: immunology
%K HIV-1: genetics
%K nef Gene Products, Human Immunodeficiency Virus: metabolism
%K nef Gene Products, Human Immunodeficiency Virus: genetics
%K nef Gene Products, Human Immunodeficiency Virus: immunology
%K Actins: metabolism
%K Receptors, Immunologic
%K DEAD Box Protein 58: metabolism
%K HIV Infections: immunology
%K HIV Infections: virology
%K HIV Infections: metabolism
%K p21-Activated Kinases: metabolism
%K Interferon-Induced Helicase, IFIH1: metabolism
%K CD4-Positive T-Lymphocytes: immunology
%K CD4-Positive T-Lymphocytes: virology
%K HEK293 Cells
%K Immunity, Innate
%K Dendritic Cells: immunology
%K Phosphorylation
%K Macrophages: immunology
%K Macrophages: virology
%K Protein Phosphatase 1: metabolism
%K Interferons: metabolism
%K Interferons: immunology
%K Virus Replication
%K nef Gene Products, Human Immunodeficiency Virus (NLM Chemicals)
%K Actins (NLM Chemicals)
%K Receptors, Immunologic (NLM Chemicals)
%K DEAD Box Protein 58 (NLM Chemicals)
%K nef protein, Human immunodeficiency virus 1 (NLM Chemicals)
%K p21-Activated Kinases (NLM Chemicals)
%K RIGI protein, human (NLM Chemicals)
%K Interferon-Induced Helicase, IFIH1 (NLM Chemicals)
%K PAK2 protein, human (NLM Chemicals)
%K IFIH1 protein, human (NLM Chemicals)
%K Protein Phosphatase 1 (NLM Chemicals)
%K Interferons (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:41354661
%R 10.1038/s41467-025-67028-5
%U https://pub.dzne.de/record/282595