Antiviral Therapy in the Hepatitis C Virus Life Cycle

Abstract and Introduction

Abstract

Advances in our understanding of the hepatitis C virus (HCV) life cycle have enabled the development of numerous clinically advanced direct-acting antivirals. Indeed, the recent approval of first-generation direct-acting antivirals that target the viral NS3–4A protease and NS5B RNA-dependent RNA polymerase brings closer the possibility of universally efficacious and well-tolerated antiviral therapies for this insidious infection. However, the complexities of comorbidities, unforeseen side effects or drug–drug interactions, viral diversity, the high mutation rate of HCV RNA replication and the elegant and constantly evolving mechanisms employed by HCV to evade host and therapeutically implemented antiviral strategies remain as significant obstacles to this goal. Here, we review advances in our understanding of the HCV life cycle and associated opportunities for antiviral therapy.

Introduction

Hepatitis C virus (HCV) is an enveloped, positive-stranded RNA virus that is the founding member of the Hepacivirus genus within the Flaviviridae family that includes other significant human pathogens such as dengue virus and West Nile virus. The approximately 9.6-kb HCV genome encodes a single large open reading frame that is flanked by 5′ and 3′ untranslated regions (UTRs) that regulate genome translation via an internal ribosome entry site (IRES) within the 5′-UTR and replication via a negative-strand RNA intermediate (Figure 1). Translation of the genome by the host ribosome machinery that recognizes the IRES yields an approximately 3000 amino acid polyprotein that is cleaved co- and post-translationally by host and viral proteases to liberate the structural proteins (core, E1 and E2), the hydrophobic peptide p7 and the nonstructural (NS) proteins (NS2, NS3, NS4A, NS4B, NS5A and NS5B).^[1] Like all positive-stranded RNA viruses, HCV infection results in modification of cytoplasmic membranes to create specialized microenvironments where viral genome replication ensues.

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Figure 1.

The hepatitis C virus genome and polyprotein processing. The HCV genome consists of a singlestranded RNA molecule of approximately 9.6kb. The ORF is flanked by 5′ and 3′ NTRs important in viral replication and translation of the HCV polyprotein via the IRES. The polyprotein is co- and post-translationally processed by host-encoded and viral proteases as indicated by the colored triangles.
HCV: Hepatitis C virus; IRES: Internal ribosome entry site; NTR: Nontranslated region; ORF: Open reading frame.

It is estimated that 130–170 million people worldwide are chronically infected with HCV. The majority of infected individuals will develop a chronic infection, which over 20–30 years causes progressive liver disease ranging from fibrosis to end-stage liver diseases such as cirrhosis and hepatocellular carcinoma.^[2] Due largely to the high degree of genetic diversity and rapid mutation rate of HCV, there is no preventative vaccine available and progress in the development of preventative and therapeutic vaccines has been slow. For more than a decade, the standard-of-care therapy for HCV infection was a combination of pegylated IFN-α and ribavirin (pegIFN-α/RBV) for up to 48 weeks. However, this treatment causes severe side effects and is only effective in eliminating viral replication in 50–80% of infected individuals, depending largely on the HCV genotype (of which there are seven) and host genetics, such as polymorphisms in the IL-28B gene locus.

A new era in HCV treatment was heralded by the approval of first-generation inhibitors of the viral NS3–4A protease (telaprevir and boceprevir) for use in combination with pegIFN-α/RBV for treatment of infections with HCV genotype 1. More recently, a second-wave NS3–4A inhibitor (simeprevir – to be used in combination with pegIFN-α/RBV) and a promising nucleotide analog inhibitor of NS5B (sofosbuvir – to be used in combination with pegIFN-α/RBV or RBV), were approved by regulatory authorities in the USA, the European Union and Canada. Furthermore, multiple promising DAAs that target NS3–4A, NS5A or NS5B are in advanced stages of clinical development and numerous antiviral compounds that target these proteins, other HCV proteins and host factors are in earlier stages of development. Accordingly, there is great hope for safe, effective, all oral, pan-genotypic and IFN-free treatment regimens in the near future. In this review, we discuss the HCV life cycle in relation to current and future targets of antiviral drug development.