A functional map of HIV-host interactions in primary human T cells

Joseph Hiatt, Judd F. Hultquist (), Michael J. McGregor, Mehdi Bouhaddou, Ryan T. Leenay, Lacy M. Simons, Janet M. Young, Paige Haas, Theodore L. Roth, Victoria Tobin, Jason A. Wojcechowskyj, Jonathan M. Woo, Ujjwal Rathore, Devin A. Cavero, Eric Shifrut, Thong T. Nguyen, Kelsey M. Haas, Harmit S. Malik, Jennifer A. Doudna, Andrew P. May, Alexander Marson () and Nevan J. Krogan ()
Additional contact information
Joseph Hiatt: University of California
Judd F. Hultquist: Northwestern University Feinberg School of Medicine
Michael J. McGregor: Gladstone Institutes
Mehdi Bouhaddou: Gladstone Institutes
Ryan T. Leenay: Chan Zuckerberg BioHub
Lacy M. Simons: Northwestern University Feinberg School of Medicine
Janet M. Young: Fred Hutchinson Cancer Research Center
Paige Haas: Gladstone Institutes
Theodore L. Roth: University of California
Victoria Tobin: University of California
Jason A. Wojcechowskyj: Gladstone Institutes
Jonathan M. Woo: University of California
Ujjwal Rathore: University of California
Devin A. Cavero: University of California
Eric Shifrut: University of California
Thong T. Nguyen: Gladstone Institutes
Kelsey M. Haas: Gladstone Institutes
Harmit S. Malik: Fred Hutchinson Cancer Research Center
Jennifer A. Doudna: Gladstone Institutes
Andrew P. May: Chan Zuckerberg BioHub
Alexander Marson: University of California
Nevan J. Krogan: Gladstone Institutes

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Human Immunodeficiency Virus (HIV) relies on host molecular machinery for replication. Systematic attempts to genetically or biochemically define these host factors have yielded hundreds of candidates, but few have been functionally validated in primary cells. Here, we target 426 genes previously implicated in the HIV lifecycle through protein interaction studies for CRISPR-Cas9-mediated knock-out in primary human CD4+ T cells in order to systematically assess their functional roles in HIV replication. We achieve efficient knockout (>50% of alleles) in 364 of the targeted genes and identify 86 candidate host factors that alter HIV infection. 47 of these factors validate by multiplex gene editing in independent donors, including 23 factors with restrictive activity. Both gene editing efficiencies and HIV-1 phenotypes are highly concordant among independent donors. Importantly, over half of these factors have not been previously described to play a functional role in HIV replication, providing numerous novel avenues for understanding HIV biology. These data further suggest that host-pathogen protein-protein interaction datasets offer an enriched source of candidates for functional host factor discovery and provide an improved understanding of the mechanics of HIV replication in primary T cells.

Date: 2022
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DOI: 10.1038/s41467-022-29346-w

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