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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Caterina Prelli Bozzo & Alexandre Laliberté & Aurora De Luna & Chiara Pastorio & Kerstin Regensburger & Stefan Krebs & Alexander Graf & Helmut Blum & Meta Volcic & Konstantin M. J. Sparrer & Frank Kir, 2024. "Replication competent HIV-guided CRISPR screen identifies antiviral factors including targets of the accessory protein Nef," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48228-x
    DOI: 10.1038/s41467-024-48228-x
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    References listed on IDEAS

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    1. Annachiara Rosa & Ajit Chande & Serena Ziglio & Veronica De Sanctis & Roberto Bertorelli & Shih Lin Goh & Sean M. McCauley & Anetta Nowosielska & Stylianos E. Antonarakis & Jeremy Luban & Federico And, 2015. "HIV-1 Nef promotes infection by excluding SERINC5 from virion incorporation," Nature, Nature, vol. 526(7572), pages 212-217, October.
    2. Stuart J. D. Neil & Trinity Zang & Paul D. Bieniasz, 2008. "Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu," Nature, Nature, vol. 451(7177), pages 425-430, January.
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