Journal
NATURE GENETICS
Volume 49, Issue 2, Pages 193-203Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3741
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Funding
- Howard Hughes Medical Institute
- National Institutes of Health [CA103866, F31 CA189437, P50 GM082250, U19 AI106754, P01 AI090935]
- National Human Genome Research Institute [2U54HG003067-10]
- National Science Foundation
- MIT Whitaker Health Sciences Fund
- UCSF Sandler Fellowship
- UCSF MPHD T32 Training Grant
- Deutsche Forschungsgemeinschaft [SCHU3020/2-1]
- NIH [P30 AI027763, P30 AI060354]
- Harvard University Center for AIDS Research [P30 AI060354]
- NIH
- NIAID
- NCI
- NICHD
- NHLBI
- NIDA
- NIMH
- NIA
- FIC
- OAR
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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 (SLC3562) 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.
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