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?:abstract
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Genome-wide CRISPR/Cas9 knock-out genetic screens are powerful approaches to unravel new regulators of viral infections. Here, we took advantage of the ability of interferon (IFN) to restrict HIV-1 infection, in order to create an environment hostile to replication and reveal new inhibitors through a CRISPR screen. This approach led to the identification of the RNA helicase DDX42 as an intrinsic inhibitor of HIV-1. Depletion of endogenous DDX42 increased HIV-1 DNA accumulation and infection in cell lines and primary cells, irrespectively of IFN treatment. DDX42 overexpression inhibited HIV-1, whereas a dominant-negative mutant of DDX42 increased infection. Importantly, DDX42 impacted retrotransposition of long interspersed elements-1 (LINE-1), infection with other retroviruses and positive-strand RNA viruses, including Chikungunya virus (CHIKV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, DDX42 did not inhibit infection with negative-strand RNA viruses such as influenza A virus (IAV), arguing against a general, unspecific effect on target cells. Proximity ligation assays showed DDX42 in the vicinity of viral elements during infection, and RNA immunoprecipitation confirmed DDX42 interaction with LINE-1 RNAs. This strongly suggested a direct mode of action of DDX42 on viral ribonucleoprotein complexes. Taken together, our results identify DDX42 as a new, broadly active intrinsic antiviral inhibitor.
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