A genome-wide CRISPR screen identifies a restricted set of HIV host dependency factors
Author(s)
Park, Ryan J; Koundakjian, Dylan; Hultquist, Judd F; Lamothe-Molina, Pedro; Monel, Blandine; Schumann, Kathrin; Yu, Haiyan; Krupzcak, Kevin M; Garcia-Beltran, Wilfredo; Piechocka-Trocha, Alicja; Krogan, Nevan J; Marson, Alexander; Hacohen, Nir; Walker, Bruce D; Wang, Tim; Sabatini, David; Lander, Eric Steven; ... Show more Show less
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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.
Date issued
2016-12Department
Massachusetts Institute of Technology. Institute for Medical Engineering & Science; Massachusetts Institute of Technology. Department of Biology; Koch Institute for Integrative Cancer Research at MITJournal
Nature Genetics
Publisher
Nature Publishing Group
Citation
Park, Ryan J et al. “A Genome-Wide CRISPR Screen Identifies a Restricted Set of HIV Host Dependency Factors.” Nature Genetics 49, 2 (December 2016): 193–203 © 2017 Nature America, Inc., part of Springer Nature
Version: Author's final manuscript
ISSN
1061-4036
1546-1718