A virally encoded high-resolution screen of cytomegalovirus dependencies

Yaara Finkel, Aharon Nachshon, Einav Aharon, Tamar Arazi, Elena Simonovsky, Martina Dobešová, Zack Saud, Avi Gluck, Tal Fisher, Richard J. Stanton, Michal Schwartz () and Noam Stern-Ginossar ()
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Yaara Finkel: Weizmann Institute of Science
Aharon Nachshon: Weizmann Institute of Science
Einav Aharon: Weizmann Institute of Science
Tamar Arazi: Weizmann Institute of Science
Elena Simonovsky: Weizmann Institute of Science
Martina Dobešová: Weizmann Institute of Science
Zack Saud: Cardiff University School of Medicine
Avi Gluck: Weizmann Institute of Science
Tal Fisher: Weizmann Institute of Science
Richard J. Stanton: Cardiff University School of Medicine
Michal Schwartz: Weizmann Institute of Science
Noam Stern-Ginossar: Weizmann Institute of Science

Nature, 2024, vol. 630, issue 8017, 712-719

Abstract: Abstract Genetic screens have transformed our ability to interrogate cellular factor requirements for viral infections1,2, but most current approaches are limited in their sensitivity, biased towards early stages of infection and provide only simplistic phenotypic information that is often based on survival of infected cells2–4. Here, by engineering human cytomegalovirus to express single guide RNA libraries directly from the viral genome, we developed virus-encoded CRISPR-based direct readout screening (VECOS), a sensitive, versatile, viral-centric approach that enables profiling of different stages of viral infection in a pooled format. Using this approach, we identified hundreds of host dependency and restriction factors and quantified their direct effects on viral genome replication, viral particle secretion and infectiousness of secreted particles, providing a multi-dimensional perspective on virus–host interactions. These high-resolution measurements reveal that perturbations altering late stages in the life cycle of human cytomegalovirus (HCMV) mostly regulate viral particle quality rather than quantity, establishing correct virion assembly as a critical stage that is heavily reliant on virus–host interactions. Overall, VECOS facilitates systematic high-resolution dissection of the role of human proteins during the infection cycle, providing a roadmap for in-depth study of host–herpesvirus interactions.

Date: 2024
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DOI: 10.1038/s41586-024-07503-z

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