(HEPATOLOGY 2011;) Hepatitis C virus (HCV) infects over 3% of the population, causing severe liver disease. Current therapy comprising pegylated interferon (IFN) and ribavirin (Rib) is inadequate, which, combined with high cost and poor patient compliance, has driven the demand for new virus-specific drugs.1 Future standard of care will replace IFN/Rib with combinations of specific inhibitors, such as seen for human immunodeficiency virus (HIV) therapy. However, extensive HCV variability raises concerns selleck screening library over the ability of relatively few compounds to suppress resistance. Thus, great effort focuses on expanding the repertoire of HCV drug targets, expedited by the availability
of the Japanese fulminant hepatitis clone 1 (JFH-1) infectious isolate.2 HCV is the prototype member of the Hepacivirus genus within the Flaviviridae.3
It is enveloped and possesses a positive-sense single-stranded RNA genome of ∼9.6 kb. An internal ribosome entry site in the 5′ untranslated region drives translation check details of a polyprotein that is cleaved into 10 mature products. The core and envelope glycoproteins with the RNA genome comprise the virion, whereas nonstructural (NS) proteins modulate host metabolism and replication of the viral RNA. JFH-1 has permitted the study of particle production, and it has become clear that, in addition to canonical virion components, other viral proteins are required.4-13 HCV p7 forms a cation channel in vitro,14-16 and both deletions and point mutations markedly reduce the production of infectious virions in culture.4, 5 It is comprised of two trans-membrane domains separated by a cytosolic loop and forms both hexameric and heptameric complexes.14, 17, 18 We have recently shown that p7 acts as a proton channel within infected cells, which is directly required for the production medchemexpress of infectious virions.19 p7 is required for HCV to replicate in chimpanzees20 and small molecules block both channel function in vitro and virion production in culture, rendering it an attractive antiviral target.21, 22 Skepticism concerning
p7 inhibitors heralds from trials where p7 inhibitor monotherapy, or combinations with IFN/Rib failed to significantly improve responses.23 However, evidence from meta-analyses24, 25 and patient virus loads at early time points26, 27 supports a specific antiviral effect, and selection of specific nonsynonymous mutations occurs within patient isolate p7 sequences.28, 29 Because HCV displays genotype (GT)-dependent p7 inhibitor sensitivity,21 changes in amino acid sequence could interfere with the binding of drug molecules, making it likely that the emergence of resistant quasispecies accounts for trial outcomes. Here, we identify p7 resistance mutations specific to adamantane and IS drugs, indicative of a genuine antiviral effect that supports their inclusion in future combination therapies.