TY  - JOUR
AU  - Laliberté, Alexandre
AU  - Prelli Bozzo, Caterina
AU  - Acharya, Dhiraj
AU  - De Luna, Aurora
AU  - Hirschenberger, Maximilian
AU  - Zhu, Junji
AU  - Volcic, Meta
AU  - Stolp, Bettina
AU  - Rodriguez-Quinteros, Cristina M
AU  - Fackler, Oliver T
AU  - Gack, Michaela U
AU  - Sparrer, Konstantin M J
AU  - Kirchhoff, Frank
TI  - Nef stabilizes actin to prevent HIV-1 sensing by RIG-I-like receptors.
JO  - Nature Communications
VL  - 16
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Springer Nature
M1  - DZNE-2025-01353
SP  - 10945
PY  - 2025
AB  - 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.
KW  - Humans
KW  - HIV-1: immunology
KW  - HIV-1: genetics
KW  - nef Gene Products, Human Immunodeficiency Virus: metabolism
KW  - nef Gene Products, Human Immunodeficiency Virus: genetics
KW  - nef Gene Products, Human Immunodeficiency Virus: immunology
KW  - Actins: metabolism
KW  - Receptors, Immunologic
KW  - DEAD Box Protein 58: metabolism
KW  - HIV Infections: immunology
KW  - HIV Infections: virology
KW  - HIV Infections: metabolism
KW  - p21-Activated Kinases: metabolism
KW  - Interferon-Induced Helicase, IFIH1: metabolism
KW  - CD4-Positive T-Lymphocytes: immunology
KW  - CD4-Positive T-Lymphocytes: virology
KW  - HEK293 Cells
KW  - Immunity, Innate
KW  - Dendritic Cells: immunology
KW  - Phosphorylation
KW  - Macrophages: immunology
KW  - Macrophages: virology
KW  - Protein Phosphatase 1: metabolism
KW  - Interferons: metabolism
KW  - Interferons: immunology
KW  - Virus Replication
KW  - nef Gene Products, Human Immunodeficiency Virus (NLM Chemicals)
KW  - Actins (NLM Chemicals)
KW  - Receptors, Immunologic (NLM Chemicals)
KW  - DEAD Box Protein 58 (NLM Chemicals)
KW  - nef protein, Human immunodeficiency virus 1 (NLM Chemicals)
KW  - p21-Activated Kinases (NLM Chemicals)
KW  - RIGI protein, human (NLM Chemicals)
KW  - Interferon-Induced Helicase, IFIH1 (NLM Chemicals)
KW  - PAK2 protein, human (NLM Chemicals)
KW  - IFIH1 protein, human (NLM Chemicals)
KW  - Protein Phosphatase 1 (NLM Chemicals)
KW  - Interferons (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41354661
DO  - DOI:10.1038/s41467-025-67028-5
UR  - https://pub.dzne.de/record/282595
ER  -