Nucleotide sequence variations in the internal ribosome entry site of hepatitis C virus-1b: No association with efficacy of interferon therapy or serum HCV-RNA levels

Abstract

The extreme 5'-proximal sequences of the hepatitis C virus (HCV) genome including the 5'untranslated region (5'UTR) and the first 30 nucleotides of the core region are highly conserved, and serve as an internal ribosome entry site (IRES) that initiates the cap-independent translation of HCV polyprotein. Mutations in the IRES sequence have been shown to cause changes in the efficiency of protein translation in vitro. However, the significance of genetic variations in the IRES is not fully known in clinical settings. Pretreatment sera of 25 patients with HCV-1b infection who were treated with interferon were amplified by polymerase chain reaction (PCR), and the IRES sequence was directly sequenced. Correlation of interferon responses or other clinical features with IRES sequence variability was studied. Eleven of 25 patients were sustained responders (SR) of interferon treatment (negative serum HCV RNA and normal alanine transaminase levels for 6 months after the end of interferon treatment), and the other 14 patients were nonresponders ([NR], defined as any patient with positive serum HCV RNA within 6 months after the end of interferon therapy). In each patient, one to four nucleotide substitutions were found compared with the consensus sequence of HCV-1b genotype. There were no differences in the number of nucleotide substitutions between either SR and NR (mean, 1.8 in SR, 2.1 in NR; P = .30), and no specific variations associated with SR or NR were observed. Although NR had significantly higher serum levels of pretreatment HCV RNA than SR (median, 16 vs. <0.5 Meq/mL; P = .02), there was no correlation between the HCV-RNA level and the number of nucleotide substitutions in the IRES (mean, 1.9 nucleotide substitutions in 12 patients with HCV RNA <0.5 Meq/ mL vs. 2.1 nucleotide substitutions in 13 patients with HCV RNA >0.5 Meq/mL; P = .61). Sequence variability of the IRES has no influence on interferon efficacy or serum HCV-RNA concentrations in patients with chronic HCV-1b infection.

IRES complexity before IFN‐alpha treatment and evolution of the viral load at the early stage of treatment in peripheral blood mononuclear cells from chronic hepatitis C patients

“…In spite of that, no significant difference in viral load (reflecting enhance of translational activity) was related to these nucleotidic sites in this study. These results agreed with what it was mentioned previously (Yamamoto et al, 1997): sequence variability of HCV-IRES was not appearing to correlate with any difference in HCV-RNA concentration in the PBMCs which reflects the level of HCV replication. Obviously, viral population has established an equilibrium between the quasispecies and immune constraints.…”

Comparative Analysis of Translation Efficiencies of Hepatitis C Virus 5′ Untranslated Regions among Intraindividual Quasispecies Present in Chronic Infection: Opposite Behaviors Depending on Cell Type

“…To date, although little work has been undertaken in that direction, the HCV 5ЈUTR appears to be an element of choice for such an approach. Contradictory conclusions have been proposed concerning a possible correlation between the sequence variability found for HCV IRESs of different genotypes and a response to interferon therapy (15,22,32). Currently, work is under way to study HCV 5Ј UTR diversity displayed in a viral quasispecies population and its dynamics toward the viral life cycle under different biological pressures.…”

Positional effect of mutations in 5'UTR of hepatitis C virus 4a on patients' response to therapy

“…Several foot-printing, toeprinting and UV cross linking assays have shown that domain Ⅲ is the most active part in RNA-protein binding where it folds to form stem-loop structures for high affinity binding to host proteins [11,[17][18][19] . Although genomic variability in HCV IRES was shown as one mechanism for escaping IFNα effects, there has been www.wjgnet.com controversy with regard to the predictive value of pretreatment IRES genomic variations in determining later response to IFNα [20] . Although domain Ⅲ harbors only 22% of the overall IRES mutations in a mixed genotype population [21] , IRES activity seems to depend more on the location of mutant nucleotides which play the most important roles in IRES activity.…”