Hepatitis C virus genetic variability and evolution

Abstract

Hepatitis C virus (HCV) has infected over 170 million people worldwide and creates a huge disease burden due to chronic, progressive liver disease. HCV is a single-stranded, positive sense, RNA virus, member of the Flaviviridae family. The high error rate of RNA-dependent RNA polymerase and the pressure exerted by the host immune system, has driven the evolution of HCV into 7 different genotypes and more than 67 subtypes. HCV evolves by means of different mechanisms of genetic variation. On the one hand, its high mutation rates generate the production of a large number of different but closely related viral variants during infection, usually referred to as a quasispecies. The great quasispecies variability of HCV has also therapeutic implications since the continuous generation and selection of resistant or fitter variants within the quasispecies spectrum might allow viruses to escape control by antiviral drugs. On the other hand HCV exploits recombination to ensure its survival. This enormous viral diversity together with some host factors has made it difficult to control viral dispersal. Current treatment options involve pegylated interferon-α and ribavirin as dual therapy or in combination with a direct-acting antiviral drug, depending on the country. Despite all the efforts put into antiviral therapy studies, eradication of the virus or the development of a preventive vaccine has been unsuccessful so far. This review focuses on current available data reported to date on the genetic mechanisms driving the molecular evolution of HCV populations and its relation with the antiviral therapies designed to control HCV infection.

Keywords: Antiviral therapy; Evolution; Hepatitis C virus; Quasispecies; RNA; Recombination.

Figure 1

Organisation of hepatitis C virus genome and hepatitis C virus polyprotein processing. Schematic representation of the 9.6 kb positive-stranded RNA genome. Simplified RNA secondary structures in the 5’ and 3’ non-coding regions (NCRs) are shown. Internal ribosome entry site (IRES)-mediated translation produces a polyprotein precursor that is processed into the mature structural and non-structural proteins. Nucleotide positions are shown by numbers on the upper part of the scheme. Amino acid positions are shown by numbers in the lower part of the scheme. The coding region is depicted by rectangles showing the corresponding encoded proteins. Solid arrowheads denote cleavages by the endoplasmic reticulum signal peptidase. The open arrowhead indicates further C-terminal processing of the core protein by signal peptide peptidase. Red stars indicate cleavages by the hepatitis C virus NS2 and NS3-4A proteases.

Figure 2

Evolutionary tree of the seven genotypes and all known subtypes of hepatitis C virus. The tree was constructed using the maximum likelihood method using GTR + I + G (general time-reversible substitution model considering invariable sites and gamma distribution) as the nucleotide substitution model that best fitted the data using a 307-nucleotide sequence from the NS5B-coding region. Sequences used for the construction of this phylogenetic tree were extracted from Yusim et al[155].

Figure 3

Viral quasispecies. A virus replicating with a high mutation rate will generate a diverse mutant repertoire over the course of a few generations. In this schematic representation, a “parental” viral genome (black filled circle) gives rise to different variants (coloured squares, prisms and stars), each linked to another one by a point mutation. The concentric circles represent replication cycles. The resulting distribution is often referred to as quasispecies “Cloud”.