The non‐structural 5A protein of hepatitis C virus

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Abstract
The non‐structural (NS)5A protein of hepatitis C virus (HCV) is cleaved, after translation, by the NS3‐encoded zinc‐dependent serine proteinase, from the NS4B protein upstream and the NS5B protein downstream. The released, mature NS5A protein is a 56 000 MW phosphoprotein (p56), which also exists within infected cells in a hyperphosphorylated form (p58). The NS5A gene has a quasispecies distribution, meaning that various NS5A sequences co‐exist, in various proportions, in infected individuals. HCV NS5A appears to be located in cytoplasmic membranes surrounding the nucleus. Its precise functions are not known. HCV non‐structural proteins, including NS5A, form a large multiprotein replication complex, which probably directs the replication of the HCV genome. HCV NS5A lacking the 146 N‐terminal amino acids is a potent transcriptional activator in vitro. NS5A can also bind to single‐strand RNA‐dependent protein kinase (PKR) and inhibit its antiviral function. An ‘interferon (IFN) sensitivity‐determining region’ has recently been postulated in the NS5A protein central region in hepatitis C virus (HCV) genotype 1b, but strongly conflicting evidence has been published. In fact, there would seem to be no such region in the NS5A protein, even though NS5A plays an important and complex role in HCV resistance to IFN. Structure–function studies are required to identify precisely how NS5A and IFN interact.

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