A genome-wide CRISPR screen identifies a restricted set of HIV host dependency factors

Ryan J. Park, Tim Wang, Dylan Koundakjian, Judd F. Hultquist, Pedro Lamothe-Molina, Blandine Monel, Kathrin Schumann, Haiyan Yu, Kevin M. Krupzcak, Wilfredo Garcia-Beltran, Alicja Piechocka-Trocha, Nevan J. Krogan, Alexander Marson, David M. Sabatini, Eric S. Lander, Nir Hacohen, Bruce D. Walker*

*Corresponding author for this work

Research output: Contribution to journalArticle

112 Scopus citations

Abstract

Host proteins are essential for HIV entry and replication and can be important nonviral therapeutic targets. Large-scale RNA interference (RNAi)-based screens have identified nearly a thousand candidate host factors, but there is little agreement among studies and few factors have been validated. Here we demonstrate that a genome-wide CRISPR-based screen identifies host factors in a physiologically relevant cell system. We identify five factors, including the HIV co-receptors CD4 and CCR5, that are required for HIV infection yet are dispensable for cellular proliferation and viability. Tyrosylprotein sulfotransferase 2 (TPST2) and solute carrier family 35 member B2 (SLC35B2) function in a common pathway to sulfate CCR5 on extracellular tyrosine residues, facilitating CCR5 recognition by the HIV envelope. Activated leukocyte cell adhesion molecule (ALCAM) mediates cell aggregation, which is required for cell-to-cell HIV transmission. We validated these pathways in primary human CD4 + T cells through Cas9-mediated knockout and antibody blockade. Our findings indicate that HIV infection and replication rely on a limited set of host-dispensable genes and suggest that these pathways can be studied for therapeutic intervention.

Original languageEnglish (US)
Pages (from-to)193-203
Number of pages11
JournalNature Genetics
Volume49
Issue number2
DOIs
StatePublished - Jan 31 2017

ASJC Scopus subject areas

  • Genetics

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    Park, R. J., Wang, T., Koundakjian, D., Hultquist, J. F., Lamothe-Molina, P., Monel, B., Schumann, K., Yu, H., Krupzcak, K. M., Garcia-Beltran, W., Piechocka-Trocha, A., Krogan, N. J., Marson, A., Sabatini, D. M., Lander, E. S., Hacohen, N., & Walker, B. D. (2017). A genome-wide CRISPR screen identifies a restricted set of HIV host dependency factors. Nature Genetics, 49(2), 193-203. https://doi.org/10.1038/ng.3741