Abstract
The development of direct-acting antivirals (DAAs) has revolutionized the state-of-the art treatment of HCV infections, with sustained virologic response rates above 90%. However, viral variants harboring substitutions referred to as resistance-associated substitutions (RASs) may be present in baseline levels and confer resistance to DAAs, thereby posing a major challenge for HCV treatment. HCV replicons have been the primary tools for discovering and evaluating the inhibitory activity of DAAs against viral replication. Interest in replicon systems has further grown as they have become indispensable for discovering genotype-specific and cross-genotype RASs. Here, we review functional replicon systems for HCV, how these replicon systems have contributed to the development of DAAs, and the characteristics and distribution of RASs for DAAs.
Highlights
The molecular cloning of hepatitis C virus (HCV) in 1989 led to advances in fundamental research to fully decipher the virus life cycle and develop treatments for its eradication (Hoofnagle et al, 1986; Choo et al, 1989; Scheel and Rice, 2013; Alazard-Dany et al, 2019)
Recommended direct-acting antivirals are listed below and include the NS3/4A inhibitors, the NS5A inhibitors, and the NS5B inhibitors of nucleoside and non-nucleoside
Not limited to, the most effective direct-acting antivirals (DAAs) that are recommended for HCV treatment include, NS3/4A protease inhibitors (PIs, names end in -previr): glecaprevir (ABT-493) (Ng et al, 2014), grazoprevir (MK-5172) (Summa et al, 2012), paritaprevir (ABT-450) (PilotMatias et al, 2015), and voxilaprevir (GS-9857) (Taylor et al, 2019); NS5A inhibitors: daclatasvir (BMS790052) (Gao et al, 2010), ledipasvir (GS-9451) (Yang et al, 2014), elbasvir (MK-8742) (Coburn et al, 2013), velpatasvir (GS5816) (Cheng et al, 2013), ombitasvir (ABT-267) (DeGoey et al, 2014), pibrentasvir (ABT-530) (Ng et al, 2014) and ruzasvir (MK-8408) (Tong et al, 2017); inhibitors of NS5B nucleoside polymerase (NPIs, names end in -buvir): sofosbuvir (GS-7977) and non-nucleoside (NNPIs): dasabuvir (?ABT-333) (Maring et al, 2009) (Figure 1)
Summary
The molecular cloning of hepatitis C virus (HCV) in 1989 led to advances in fundamental research to fully decipher the virus life cycle and develop treatments for its eradication (Hoofnagle et al, 1986; Choo et al, 1989; Scheel and Rice, 2013; Alazard-Dany et al, 2019). Not limited to, the most effective DAAs that are recommended for HCV treatment include, NS3/4A protease inhibitors (PIs, names end in -previr): glecaprevir (ABT-493) (Ng et al, 2014), grazoprevir (MK-5172) (Summa et al, 2012), paritaprevir (ABT-450) (PilotMatias et al, 2015), and voxilaprevir (GS-9857) (Taylor et al, 2019); NS5A inhibitors (names end in -asvir): daclatasvir (BMS790052) (Gao et al, 2010), ledipasvir (GS-9451) (Yang et al, 2014), elbasvir (MK-8742) (Coburn et al, 2013), velpatasvir (GS5816) (Cheng et al, 2013), ombitasvir (ABT-267) (DeGoey et al, 2014), pibrentasvir (ABT-530) (Ng et al, 2014) and ruzasvir (MK-8408) (Tong et al, 2017); inhibitors of NS5B nucleoside polymerase (NPIs, names end in -buvir): sofosbuvir (GS-7977) and non-nucleoside (NNPIs): dasabuvir (?ABT-333) (Maring et al, 2009) (Figure 1) These DAAs exhibited subnanomolar 50% effective concentrations (EC50s) toward replicons expressing a wide range of HCV GTs with minimal cytotoxicity. The NS5A amino acid substitutions M28T/V and Q30D/E/H/R/K in the GT1a replicon yielded moderate to high resistance to ruzasvir, daclatasvir, ledipasvir, ombitasvir, elbasvir, and pibrentasvir, while L31M/V to GT1b, whereas Y93H/N/C in both the GT1 replicons conferred negligible to significantly high resistance
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