Pretreatment virus load and multiple amino acid substitutions in the interferon sensitivity-determining region predict the outcome of interferon treatment in patients with chronic genotype 1b hepatitis C virus infection

Abstract

biochemical and histological improvement. 3,4 Several factors Hepatitis C virus (HCV) genotype 1b and high precan predict a poor response to interferon therapy, e.g., high treatment virus load are predictive factors of poor repretreatment virus load, genotype 1b, advanced histological sponse to interferon therapy in patients with chronic changes, lower serum ferritin level, and a high degree of hepatitis C. To further examine the factors predicting amino acid substitutions of the hypervariable region (for rethe response to interferon in patients with genotype 1b view, see Davis 5). infection, we analyzed 110 consecutive patients withRecently, Enomoto et al. 6 compared amino acid sequences HCV who were treated with a total of 624 million units of of interferon-sensitive and -resistant quasispecies by analyzlymphoblastoid interferon alfa. Thirty-six patients (33%) ing serum samples of three patients infected with genotype were responders, while the remaining 74 patients (67%)1b HCV before and after interferon therapy. They identified were nonresponders. Multivariate analysis showed that in the interferon-sensitive strains of HCV clusters of amino a high virus titer (assessed by serum core protein level, acid substitutions in the carboxyl terminal half of the NS5A P Å .0021) and the presence of more than two amino acid region (codon 2154-2383). They also detected multiple missubstitutions in the interferon sensitivity-determining sense mutations exclusively in a 40-amino acid stretch (coregion (ISDR) (P Å .0036) correlated significantly with don 2209-2248) in interferon-sensitive HCV isolates. 6,7 In the response to interferon therapy. Because mutations contrast, the sequences of interferon-resistant HCV strains analyzed by direct sequencing of polymerase chain reacwere identical to those of prototype genotype 1b. They desigtion (PCR) products may reflect artifacts of direct senated the region with these amino acid substitutions as the quencing, we further analyzed quasispecies of HCV in interferon sensitivity-determining region (ISDR) 6 and this region by cloning and sequencing. Although PCRshowed, by multivariate analysis, that the substitution in based analysis of responders with multiple amino acid the ISDR was the best predictive factor of the response to substitutions in the ISDR showed the presence of a small interferon therapy. 7 These results were potentially of great amount of wild-type strain in their serum, the results importance but were based on relatively few patients treated obtained by direct sequencing and cloning were essenwith varying regimens of interferon. To provide further evitially the same. A longitudinal study of quasispecies in dence for or against the predictive power of amino acid substi-2 patients who showed a dramatic change in the virus titer showed no conversion from wild type to mutant or tutions in the ISDR, we used a large sample of patients with vice versa. Our results indicate that amino acid substitu-HCV genotype 1b seen in our unit who were treated with a tions and virus ...

Quasispecies evolution in NS5A region of hepatitis C virus genotype 1b during interferon or combined interferon-ribavirin therapy

“…This sequence has been termed the interferon sensitivity-determining region (ISDR). These results were then confirmed by other Japanese studies [11][12][13][14][15] , but were never in accordance with most Western European [16][17][18][19][20] and American studies [21][22][23] , in which most of the ISDR sequences harbored an intermediate profile.…”

Mutations in nonstructural protein 5A gene and response to interferon in hepatitis C virus genotype 2 infection

“…39 ISDR mutations are also shown to be related to the serum HCV-RNA levels. 13,16 Therefore, in HCV-2 infection, the amino acid changes in the homologous region might also be associated with the effect of interferon therapy. The present analysis of the C-terminal half of NS5A of HCV-2 confirmed that there is a significant association among the effect of interferon therapy, serum HCV-RNA levels, and the amino acid changes in NS5A2163-2228 of HCV-2a (the corresponding region of ISDR of HCV-1b, NS5A2193-2228 plus its upstream region) or NS5A2193-2228 alone.…”

“…The present findings of HCV-2a infection on the interrelationship among interferon efficacy, viral load, and NS5A mutations are consistent with the observation seen in HCV1b. 13,16,39 The mechanism of this interrelation is still unclear, but an association between the amino acid changes in NS5A and reduced serum HCV-RNA level suggest an important role of the NS5A protein in the proliferation of HCV. Otherwise, the NS5A protein would confer the resistance to antiviral effects of interferon.…”

“…In previous studies, interferon effect and pretreatment viral load were also associated with the mutations in ISDR in HCV-1b. 13,16 Thus, the relation between NS5A structure and interferon effect or viral load in HCV genotypes other than HCV-1b is of great interest.Several studies that focused on biological functions of NS5A revealed some aspects of its properties. In particular, Gale et al 17 suggested that the NS5A protein inhibits an RNA-dependent protein kinase (PKR), which plays a major role in the viral protection by inhibiting viral protein translation.…”

“…In previous studies, interferon effect and pretreatment viral load were also associated with the mutations in ISDR in HCV-1b. 13,16 Thus, the relation between NS5A structure and interferon effect or viral load in HCV genotypes other than HCV-1b is of great interest.…”