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Natural hepatitis C virus (HCV) infection is restricted to humans, whereas other primates such as rhesus macaques are non-permissive for infection. To identify human and rhesus macaque genes that differ or share the ability to inhibit HCV replication, we conducted a medium-throughput screen of lentivirus-expressed host genes that disrupt replication of HCV subgenomic replicon RNA expressing secreted <i>Gaussia</i> luciferase. A combined total of >800 interferon-stimulated genes (ISGs) were screened. Our findings confirmed established anti-HCV ISGs, such as <i>IRF1</i>, <i>PKR</i> and <i>DDX60</i>. Novel species–specific inhibitors were also identified and independently validated. Using a cell-based system that recapitulates productive HCV infection, we identified that over-expression of the ‘Rho Guanine Nucleotide Exchange Factor 3’ gene (<i>ARHGEF3</i>) from both species inhibits full-length virus replication. Additionally, replication of two mosquito-borne flaviviruses, yellow fever virus (YFV) and Zika virus (ZIKV), were also reduced in cell lines over-expressing <i>ARHGEF3</i> compared to controls. In conclusion, we ascribe novel antiviral activity to the cellular gene <i>ARHGEF3</i> that inhibits replication of HCV and other important human viral pathogens belonging to the <i>Flaviviridae</i>, and which is conserved between humans and rhesus macaques.