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

作者：Park Ryan J; Wang Tim; 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; Sabatini David M^*; Lander Eric S^*; Hacohen Nir^*; Walker Bruce D^*

来源：Nature Genetics, 2017, 49(2): 193-203.

DOI：10.1038/ng.3741

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.

• 出版日期2017-2
• 单位MIT; 河北医科大学