The family Flaviviridae consists of three viral genera, Flavivirus, Pestivirus, and Hepatitis C virus (HCV), with a total of more than 70 viruses, most of which have their polyproteins organized in a similar way. This processing forms ten functional proteins, including the three structural proteins, Capsid (C), Pre-membrane (prM), and Envelope (E), and seven non-structural proteins, which include NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5. This RNA genome encodes a single open reading frame that is translated at the Endoplasmic Reticulum (ER) to give rise to a polyprotein, which is subsequently cleaved by viral and host cell proteases. The family Flaviviridae constitutes many enveloped single-stranded positive-sense RNA viruses. Here, we review the insights from various Genome-wide CRISPR screens that have advanced our understanding of Flavivirus-Host interactions. The ease, rapidity, and high reproducibility of CRISPR technology have made it an excellent tool for carrying out genome-wide screens to identify and characterize viral host dependency factors systematically. Clustered regularly interspaced short palindromic repeats (CRISPR) technology has provided an effective means of producing customizable genetic modifications and performing forward genetic screens in a broad spectrum of cell types and organisms. Since inhibiting the host dependency factors or activating the host restriction factors can suppress the viral replication and propagation in the cell, identifying them reveals potential targets for antiviral therapeutics. Therefore, studying the host cellular factors that promote or restrict their replication and pathogenesis becomes vital. Like any other virus, they are obligate intracellular parasites. Flaviviruses comprise several important human pathogens which cause significant morbidity and mortality worldwide.
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