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. MayAlexander Marson*, Nevan J. Krogan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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.

Original languageEnglish
Article number1752
JournalNature Communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022
Externally publishedYes

Funding

FundersFunder number
Mathilde Krim amfAR1110189-69-RKRL, 109504-61-RKRL
UCSF-Gladstone Institute of Virology & Immunology Center for AIDS Research
University of California, Berkeley Macrolab
National Institutes of Health
National Institute on Drug AbuseDP2 DA042423-01
National Institute of General Medical SciencesP01 AI063302, P50 GM082250, R01 AI120694
National Institute of Allergy and Infectious DiseasesP30AI027763, K22 AI136691, R01 AI150998, R01 AI165236
Burroughs Wellcome Fund
Cancer Research Institute
Simons Foundation
Gilead Sciences
Center for AIDS Research, University of WashingtonP30 AI027763
University of California, San FranciscoT32GM007618
Innovative Genomics Institute
Parker Institute for Cancer Immunotherapy11349, 1470
Third Coast Center for AIDS ResearchP30 AI117943

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