Replication competent HIV-guided CRISPR screen identifies antiviral factors including targets of the accessory protein Nef

Caterina Prelli Bozzo, Alexandre Laliberté, Aurora De Luna, Chiara Pastorio, Kerstin Regensburger, Stefan Krebs, Alexander Graf, Helmut Blum, Meta Volcic, Konstantin M. J. Sparrer () and Frank Kirchhoff ()
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Caterina Prelli Bozzo: Ulm University Medical Center
Alexandre Laliberté: Ulm University Medical Center
Aurora De Luna: Ulm University Medical Center
Chiara Pastorio: Ulm University Medical Center
Kerstin Regensburger: Ulm University Medical Center
Stefan Krebs: LMU Munich
Alexander Graf: LMU Munich
Helmut Blum: LMU Munich
Meta Volcic: Ulm University Medical Center
Konstantin M. J. Sparrer: Ulm University Medical Center
Frank Kirchhoff: Ulm University Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Innate antiviral factors are essential for effective defense against viral pathogens. However, the identity of major restriction mechanisms remains elusive. Current approaches to discover antiviral factors usually focus on the initial steps of viral replication and are limited to a single round of infection. Here, we engineered libraries of >1500 replication-competent HIV-1 constructs each expressing a single gRNAs to target >500 cellular genes for virus-driven discovery of antiviral factors. Passaging in CD4+ T cells robustly enriched HIV-1 encoding sgRNAs against GRN, CIITA, EHMT2, CEACAM3, CC2D1B and RHOA by >50-fold. Using an HIV-1 library lacking the accessory nef gene, we identified IFI16 as a Nef target. Functional analyses in cell lines and primary CD4+ T cells support that the HIV-driven CRISPR screen identified restriction factors targeting virus entry, transcription, release and infectivity. Our HIV-guided CRISPR technique enables sensitive discovery of physiologically relevant cellular defense factors throughout the entire viral replication cycle.

Date: 2024
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DOI: 10.1038/s41467-024-48228-x

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