biostudies-literatureBonaventure BInstitut des sciences biologiquesEuropean Research CouncilAgence Nationale de la RechercheAgence Nationale de Recherches sur le Sida et les Hépatites ViralesInstitut National de la Santé et de la Recherche MédicaleUniversité de MontpellierFondation pour la Recherche Médicalee54061https://www.ebi.ac.uk/biostudies/studies/S-EPMC9638865biostudies-literatureUnknown23(11)Genome-wide screens are powerful approaches to unravel regulators of viral infections. Here, a CRISPR screen identifies the RNA helicase DDX42 as an intrinsic antiviral inhibitor of HIV-1. Depletion of endogenous DDX42 increases HIV-1 DNA accumulation and infection in cell lines and primary cells. DDX42 overexpression inhibits HIV-1 infection, whereas expression of a dominant-negative mutant increases infection. Importantly, DDX42 also restricts LINE-1 retrotransposition and infection with other retroviruses and positive-strand RNA viruses, including CHIKV and SARS-CoV-2. However, DDX42 does not impact the replication of several negative-strand RNA viruses, arguing against an unspecific effect on target cells, which is confirmed by RNA-seq analysis. Proximity ligation assays show DDX42 in EMBO reportsThe DEAD box RNA helicase DDX42 is an intrinsic inhibitor of positive-strand RNA viruses.PMC9638865FDT202106013175FDT201904008024ANR‐10‐INBS‐09ECTZ35478ECTZ21792759226Lacroix LRebendenne ADjilli WMoncorge OJouvenet NMcKellar JLavigne MArnaud-Arnould MRialle SRicci EPBonaventure BSchulz RChaves Valadao ALGracias SBlaise MParrinello HGoujon CPaillart JCBriant LCourgnaud VTauziet MLabaronne EGarcia de Gracia FVivet-Boudou VBernard EGros NfalseThe DEAD box RNA helicase DDX42 is an intrinsic inhibitor of positive-strand RNA viruses.Genome-wide screens are powerful approaches to unravel regulators of viral infections. Here, a CRISPR screen identifies the RNA helicase DDX42 as an intrinsic antiviral inhibitor of HIV-1. Depletion of endogenous DDX42 increases HIV-1 DNA accumulation and infection in cell lines and primary cells. DDX42 overexpression inhibits HIV-1 infection, whereas expression of a dominant-negative mutant increases infection. Importantly, DDX42 also restricts LINE-1 retrotransposition and infection with other retroviruses and positive-strand RNA viruses, including CHIKV and SARS-CoV-2. However, DDX42 does not impact the replication of several negative-strand RNA viruses, arguing against an unspecific effect on target cells, which is confirmed by RNA-seq analysis. Proximity ligation assays show DDX42 in 2022-01-01T00:00:00Z2022 Nov2026-05-28T01:07:51.833Z2025-04-19T22:47:07.804ZS-EPMC96388653616144610.15252/embr.202154061