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A Virus-Packageable CRISPR Screen Identifies Host Factors Mediating Interferon Inhibition of HIV

By Molly Ohainle, Louisa Pendergast, Jolien Vermiere, Ferdinand Roesch, Daryl Humes, Ryan Basom, Jeffrey J. Delrow, Julie Overbaugh, Michael Emerman

Posted 20 Jul 2018
bioRxiv DOI: 10.1101/363432 (published DOI: 10.7554/elife.39823)

Interferon (IFN) inhibits HIV replication by inducing an array of antiviral effectors. Here we describe a novel CRISPR knockout screening approach to identify the ensemble of these HIV restriction factors. We assembled a CRISPR sgRNA library specific for Interferon Stimulated Genes (ISGs) into a modified lentiviral vector that allows for packaging of sgRNA-encoding genomes in trans into budding HIV-1 particles. We observed that knockout of Zinc Antiviral Protein (ZAP) improved the performance of the screen due to ZAP-mediated inhibition of the vector. We identify a small panel of IFN-induced HIV restriction factors, including MxB, IFITM1, Tetherin/BST2 and TRIM5 which together explain the inhibitory effects of IFN on the HIV-1 LAI strain in THP-1 cells. Further, we identify novel HIV dependency factors, including SEC62 and TLR2. The ability of IFN-induced restriction factors to inhibit an HIV strain to replicate in human cells suggests that these human restriction factors are incompletely antagonized.

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