Therapy Implications of Hepatitis C Virus Genetic Diversity

Abstract

Hepatitis C virus (HCV) is an important human pathogen with a high chronicity rate. An estimated 71 million people worldwide are living with chronic hepatitis C (CHC) infection, which carries the risk of progression to hepatic fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Similar to other RNA viruses, HCV has a high rate of genetic variability generated by its high mutation rate and the actions of evolutionary forces over time. There are two levels of HCV genetic variability: intra-host variability, characterized by the distribution of HCV mutant genomes present in an infected individual, and inter-host variability, represented by the globally circulating viruses that give rise to different HCV genotypes and subtypes. HCV genetic diversity has important implications for virus persistence, pathogenesis, immune responses, transmission, and the development of successful vaccines and antiviral strategies. Here we will discuss how HCV genetic heterogeneity impacts viral spread and therapeutic control.

Keywords: HCV; genetic diversity; quasispecies; therapy.

Figure 1

Hepatitis C virus (HCV) genome structure. The HCV RNA genome encodes a protein of ~3000 amino acids in length, which is cleaved to generate three structural proteins (core, E1, and E2) and seven non-structural (NS) proteins (p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B). In this figure, the amino acid positions of these proteins are mapped, and the 5’ untranslated region (5’-UTR) and 3′ untranslated region (3’-UTR) are indicated. Approved antiviral agents directly target NS3/4A, NS5A, and NS5B for effective inhibition of HCV replication.

Figure 2

Schematic representation of the genome composition of a virus population. Viral genomes are represented as horizontal lines, and mutations as symbols in the lines. (A) A homogeneous virus population in which no mutations are generated, such that all genomes within this population are identical. (B) A heterogeneous virus population in which mutants are generated at a high frequency, such that most of the genomes are genetically different. However, the average consensus sequence of this population is identical to in the homogeneous population (A). (C) The selection of an individual genome (marked in red), via random drift or positive selection, generates a new distribution of variants if the replication system produces new mutations. Now, the average population genome sequence is different from that shown in panels (A,B).