Journal Article

DZNE-2025-01353

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Nef stabilizes actin to prevent HIV-1 sensing by RIG-I-like receptors.

Laliberté, A. ; Prelli Bozzo, C. ; Acharya, D. ; De Luna, A.Extern* ; Hirschenberger, M.Extern* ; Zhu, J. ; Volcic, M. ; Stolp, B. ; Rodriguez-Quinteros, C. M. ; Fackler, O. T. ; Gack, M. U. ; Sparrer, K. M. J.DZNE* ; Kirchhoff, F.

2025
Springer Nature [London]

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Please use a persistent id in citations: 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.

Keyword(s): Humans (MeSH) ; HIV-1: immunology (MeSH) ; HIV-1: genetics (MeSH) ; nef Gene Products, Human Immunodeficiency Virus: metabolism (MeSH) ; nef Gene Products, Human Immunodeficiency Virus: genetics (MeSH) ; nef Gene Products, Human Immunodeficiency Virus: immunology (MeSH) ; Actins: metabolism (MeSH) ; Receptors, Immunologic (MeSH) ; DEAD Box Protein 58: metabolism (MeSH) ; HIV Infections: immunology (MeSH) ; HIV Infections: virology (MeSH) ; HIV Infections: metabolism (MeSH) ; p21-Activated Kinases: metabolism (MeSH) ; Interferon-Induced Helicase, IFIH1: metabolism (MeSH) ; CD4-Positive T-Lymphocytes: immunology (MeSH) ; CD4-Positive T-Lymphocytes: virology (MeSH) ; HEK293 Cells (MeSH) ; Immunity, Innate (MeSH) ; Dendritic Cells: immunology (MeSH) ; Phosphorylation (MeSH) ; Macrophages: immunology (MeSH) ; Macrophages: virology (MeSH) ; Protein Phosphatase 1: metabolism (MeSH) ; Interferons: metabolism (MeSH) ; Interferons: immunology (MeSH) ; Virus Replication (MeSH) ; nef Gene Products, Human Immunodeficiency Virus ; Actins ; Receptors, Immunologic ; DEAD Box Protein 58 ; nef protein, Human immunodeficiency virus 1 ; p21-Activated Kinases ; RIGI protein, human ; Interferon-Induced Helicase, IFIH1 ; PAK2 protein, human ; IFIH1 protein, human ; Protein Phosphatase 1 ; Interferons

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Contributing Institute(s):

1. Neurovirology and Neuroinflammation (AG Sparrer)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)

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