TitleA genome-wide CRISPR screen identifies a restricted set of HIV host dependency factors.
Publication TypeJournal Article
Year of Publication2017
AuthorsPark RJ, Wang T, Koundakjian D, Hultquist JF, Lamothe-Molina P, Monel B, Schumann K, Yu H, Krupzcak KM, Garcia-Beltran W, Piechocka-Trocha A, Krogan NJ, Marson A, Sabatini DM, Lander ES, Hacohen N, Walker BD
JournalNat Genet
Volume49
Issue2
Pagination193-203
Date Published2017 Feb
ISSN1546-1718
KeywordsActivated-Leukocyte Cell Adhesion Molecule, Cell Line, Clustered Regularly Interspaced Short Palindromic Repeats, Genome, HIV Infections, HIV-1, Host-Pathogen Interactions, Humans, Membrane Proteins, Receptors, CCR5, RNA Interference, Sulfotransferases, Virus Replication
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.

DOI10.1038/ng.3741
Alternate JournalNat. Genet.
PubMed ID27992415
PubMed Central IDPMC5511375
Grant ListR01 CA103866 / CA / NCI NIH HHS / United States
T32 AI060537 / AI / NIAID NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
P50 GM082250 / GM / NIGMS NIH HHS / United States
F31 AI116366 / AI / NIAID NIH HHS / United States
P30 AI027763 / AI / NIAID NIH HHS / United States
U19 AI106754 / AI / NIAID NIH HHS / United States
F31 CA189437 / CA / NCI NIH HHS / United States
P30 AI060354 / AI / NIAID NIH HHS / United States
P01 AI090935 / AI / NIAID NIH HHS / United States