Impact of hepatitis C virus heterogeneity on interferon sensitivity: an overview

Abstract

Hepatitis C virus (HCV) is a major cause of liver disease worldwide. HCV is able to evade host defense mechanisms, including both innate and acquired immune responses, to establish persistent infection, which results in a broad spectrum of pathogenicity, such as lipid and glucose metabolism disorders and hepatocellular carcinoma development. The HCV genome is characterized by a high degree of genetic diversity, which can be associated with viral sensitivity or resistance (reflected by different virological responses) to interferon (IFN)-based therapy. In this regard, it is of importance to note that polymorphisms in certain HCV genomic regions have shown a close correlation with treatment outcome. In particular, among the HCV proteins, the core and nonstructural proteins (NS) 5A have been extensively studied for their correlation with responses to IFN-based treatment. This review aims to cover updated information on the impact of major HCV genetic factors, including HCV genotype, mutations in amino acids 70 and 91 of the core protein and sequence heterogeneity in the IFN sensitivity-determining region and IFN/ribavirin resistance-determining region of NS5A, on virological responses to IFN-based therapy.

Keywords: Core protein; Genotype; Hepatitis C virus; Interferon; Interferon sensitivity-determining region; Interferon/ribavirin resistance-determining region; Nonstructural proteins 5A.

Figure 1

Average values of sustained virological response to pegylated-interferon and ribavirin combination therapy in patients infected with different hepatitis C virus genotypes. Average of sustained virological response (SVR) rates were calculated based on SVR rates achieved in clinical studies cited in references for genotype 1 (GT1)[30,31,37,152-154], GT2[32,155-160], GT3[32,155-158,160], GT4[30,38-40,161-163], GT5[164,165] and GT6[166-172]. In those studies, standard 48-wk treatment regimens were used for GT1 and GT4, and 24-wk treatment regimens were used for GT2 and GT3. Since the treatment regimens for GT5 and GT6 have not been established yet, the treatment duration varied among different studies where it ranged from 24 to 52 wk. HCV: Hepatitis C virus.

Figure 2

Probability of different aa residues at positions 70 (A) and 91 (B) of the core protein of different hepatitis C virus subtypes. The probability was estimated based on the core protein sequences available in hepatitis C virus (HCV) database (http://hcv.lanl.gov/content/index). The length of an aa symbol-letter represents its probability for a given HCV subtype. R: Arginine; Q: Glutamine; H: Histidine; L: Leucine; C: Cysteine; M: Methionine.

Figure 3

Sequence alignment of interferon sensitivity-determining region of major hepatitis C virus subtypes. References of aligned sequences are: hepatitis C virus (HCV)-1b, Enomoto et al[90]; HCV-1a, AF009606; HCV-2a and -2b, Murakami et al[104]; HCV-3a, GU814263; HCV-4a, El-Shamy et al[73]; HCV-5a, AF064490; HCV-6a, DQ480512. ISDR: Interferon sensitivity-determining region.

Figure 4

Sequence alignment of interferon/ribavirin resistance-determining region and its vicinity of major hepatitis C virus subtypes. The residues in interferon/ribavirin resistance-determining region (IRRDR) are written in bold face letters. References of aligned sequences are: hepatitis C virus (HCV)-1b, El-Shamy et al[122]; HCV-1a, AF009606; HCV-2a and -2b, Murakami et al[104]; HCV-3a, GU814263; HCV-4a, El-Shamy et al[73]; HCV-5a, AF064490; HCV-6a, DQ480512.