The role of HCV proteins on treatment outcomes

Abstract

For many years, the standard of treatment for hepatitis C virus (HCV) infection was a combination of pegylated interferon alpha (Peg-IFN-α) and ribavirin for 24-48 weeks. This treatment regimen results in a sustained virologic response (SVR) rate in about 50% of cases. The failure of IFN-α-based therapy to eliminate HCV is a result of multiple factors including a suboptimal treatment regimen, severity of HCV-related diseases, host factors and viral factors. In recent years, advances in HCV cell culture have contributed to a better understanding of the viral life cycle, which has led to the development of a number of direct-acting antiviral agents (DAAs) that target specific key components of viral replication, such as HCV NS3/4A, HCV NS5A, and HCV NS5B proteins. To date, several new drugs have been approved for the treatment of HCV infection. Application of DAAs with IFN-based or IFN-free regimens has increased the SVR rate up to >90% and has allowed treatment duration to be shortened to 12-24 weeks. The impact of HCV proteins in response to IFN-based and IFN-free therapies has been described in many reports. This review summarizes and updates knowledge on molecular mechanisms of HCV proteins involved in anti-IFN activity as well as examining amino acid variations and mutations in several regions of HCV proteins associated with the response to IFN-based therapy and pattern of resistance associated amino acid variants (RAV) to antiviral agents.

Fig. 1

HCV genomic organization, HCV proteins and targets for direct-acting antiviral agents. The HCV genome, having approximately 9.6 kilobases (kb), contains a 5'-nontranslated region (NTR), an internal ribosome entry site (IRES), a long open reading frame encoding polyprotein precursor of about 3,000 amino acid residues and a 3'-NTR. The polyprotein precursor is processed by both host and viral enzymes to release functional structural and non-structural proteins. HCV NS3/4A, HCV NS5A, and HCV NS5B are targets for antiviral agents [1, 2]

Fig. 2

Classical pathways of type I IFN induction and HCV mediating IFN resistance. HCV dsRNA is detected by the retinoic acid inducible gene I (RIG-I) and the toll-like receptor 3 (TLR3) and subsequently triggers the cascade of adaptor proteins, mitochondrial antiviral signaling protein (MAVS) and TIR-domain containing adapter-inducing interferon-β (TRIF), respectively. This leads to the activation of the type I IFN induction pathway. Binding of IFNs to their cellular receptors activates an intracellular signaling cascade via the Jak/STAT signaling pathway and leads to the up-regulation of a number of interferon-stimulated genes (ISGs) expression [–82]

Fig. 3

HCV NS5A protein. Several regions within the NS5A proteins of HCV play a role in the IFN sensitivity of HCV including the interferon-sensitivity-determining region (ISDR; codons 2209–2248 of HCV genome corresponding to amino acid residues 237–276 of NS5A protein), the interferon and ribavirin resistance determining region (IRRDR; codons 2334–2379 or amino acid residues 362–407 of NS5A), the protein kinase R binding domain (PKRBD; codons 2209–2274 or amino acid residues 237–302 of NS5A), and the variable region 3 (V3; codons 2353–2379 or amino acid residues 381–407 of NS5A) [17, 98, 123, 135, 137]