Three antiviral targets in the HCV replication complex deliver pangenotypic 8-12 week cures: (1) NS3/4A serine protease — cleaves the HCV polyprotein into functional non-structural proteins (the -previrs); (2) NS5A protein — multifunctional in RNA replication + virion assembly (the -asvirs); (3) NS5B RNA-dependent RNA polymerase — nucleoside analog target (sofosbuvir, covered in AV-1) or non-nucleoside allosteric site (the -buvirs). Modern combinations (sofosbuvir/velpatasvir = Epclusa; sofosbuvir/ledipasvir = Harvoni; glecaprevir/pibrentasvir = Mavyret; elbasvir/grazoprevir = Zepatier) deliver >95% SVR12 across genotypes 1-6.
Organ Systems
digestive
immune-hematologic
Pathway Steps
hcv-polyprotein → hcv-nonstructural-proteins — via NS3/4A serine protease cleaves polyprotein; protease-inhibitor target. HCV translates its genome as a single polyprotein, cleaved (by host signal peptidases and the viral NS3/4A protease) into structural and nonstructural (NS) proteins. The NS proteins build the replication machinery — and NS3/4A protease is the target of the “-previr” direct-acting antivirals.
hcv-rna → hcv-rna-replication — via NS5B RNA-dependent RNA polymerase + NS5A scaffolding. The NS5B RNA-dependent RNA polymerase (with the NS5A assembly factor) replicates the viral RNA genome. NS5B inhibitors (“-buvir”, e.g. sofosbuvir) and NS5A inhibitors (“-asvir”) target these — combinations now cure >95% of HCV, a landmark of antiviral therapy.