Genetic diversity of the hepatitis C virus: Impact and issues in the antiviral therapy

Abstract

The hepatitis C Virus (HCV) presents a high degree of genetic variability which is explained by the combination of a lack of proof reading by the RNA dependant RNA polymerase and a high level of viral replication. The resulting genetic polymorphism defines a classification in clades, genotypes, subtypes, isolates and quasispecies. This diversity is known to reflect the range of responses to Interferon therapy. The genotype is one of the predictive parameters currently used to define the antiviral treatment strategy and the chance of therapeutic success. Studies have also reported the potential impact of the viral genetic polymorphism in the outcome of antiviral therapy in patients infected by the same HCV genotype. Both structural and non structural genomic regions of HCV have been suggested to be involved in the Interferon pathway and the resistance to antiviral therapy. In this review, we first detail the viral basis of HCV diversity. Then, the HCV genetic regions that may be implicated in resistance to therapy are described, with a focus on the structural region encoded by the E2 gene and the non-structural genes NS3, NS5A and NS5B. Both mechanisms of the Interferon resistance and of the new antiviral drugs are described in this review.

Hepatitis C virus genetic variability and evolution

“…The most variable region of the genome is the one that codes for the membrane glycoproteins E1 and E2 [27] . The sequences belonging to the hypervariable regions 1 and 2 (HVR1 and HVR2) of E2 gene are the ones that show less sequence homology with only 50% identity between different isolates [28] . Factors that may contribute to high genetic variability of these viruses include large population sizes, short generation times and high replication rates [29] .…”

An update on hepatitis C virus

“…It displays enormous genetic diversity, which results from a high mutation rate and a high replication rate. 2,3 Comparison of nucleotide sequences and phylogenetics of global HCV sequences has revealed seven different strains or genotypes differing by 30-35% of nucleotide ABSTRACT sites. Within each genotype, there are further divisions into subtypes (more than 67 subtypes) that differ by 10-15%.…”

Molecular Evolution of Hepatitis Viruses

“…HCV has been classified in 7 genotypes, according to a genetic divergence of more than 30-35% in the complete genome and in several subtypes inside each genotype, according to divergences of more than 20% (Figure 8) (Le Guillou-Guillemette et al, 2007;Chayama & Hayes, 2011). Infections with HCV genotype 1 are associated with the lowest therapeutic success (Zeuzem et al, 2000).…”