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

✍ Scribed by C Yamamoto; N Enomoto; M Kurosaki; S Yu; J Tazawa; N Izumi; F Marumo; C Sato

• Publisher: John Wiley and Sons
• Year: 1997
• Tongue: English
• Weight: 207 KB
• Volume: 26
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.510260633

✦ Synopsis

The extreme 5-proximal sequences of the hepatitis C virus RNA concentrations in patients with chronic HCV-1b infection. (HEPATOLOGY 1997;26:1616-1620.) (HCV) genome including the 5untranslated region (5UTR) and the first 30 nucleotides of the core region are highly conserved, and serve as an internal ribosome entry site (IRES)

Hepatitis C virus (HCV) is a positive, single-stranded RNA that initiates the cap-independent translation of HCV polyprovirus, with the HCV-RNA genome itself serving as messenger tein. Mutations in the IRES sequence have been shown to RNA in the infected hepatocyte. 1,2 The 5untranslated region cause changes in the efficiency of protein translation in vitro. (5UTR) of the HCV genome is 341 nucleotides long, and is However, the significance of genetic variations in the IRES is the most conserved region throughout the HCV genome not fully known in clinical settings. Pretreatment sera of 25 among different HCV genotypes. 3 The 5UTR together with patients with HCV-1b infection who were treated with interthe first 30 nucleotides of the core region acts as an internal feron were amplified by polymerase chain reaction (PCR), ribosome entry site (IRES) regulating the cap-independent and the IRES sequence was directly sequenced. Correlation translation of HCV RNA to polyprotein in a manner similar of interferon responses or other clinical features with IRES to that of picornavirus. 4,5 sequence variability was studied. Eleven of 25 patients were Recently, a detailed analysis of the IRES function revealed sustained responders (SR) of interferon treatment (negative that the binding of pyrimidine-binding protein, 6 La antigen, 7 serum HCV RNA and normal alanine transaminase levels for or other cellular proteins 8 to the IRES is necessary for its 6 months after the end of interferon treatment), and the other function. Mutagenesis analysis suggested that changes in sec-14 patients were nonresponders ([NR], defined as any patient ondary or tertiary structure of IRES as well as changes in with positive serum HCV RNA within 6 months after the end primary nucleotide sequence would interfere with the bindof interferon therapy). In each patient, one to four nucleotide ing of these proteins, resulting in a decrease of the efficiency substitutions were found compared with the consensus seof protein translation. 8,9 Therefore, nucleotide substitutions quence of HCV-1b genotype. There were no differences in the in the IRES, if they exist, could correlate with clinically signifnumber of nucleotide substitutions between either SR and icant findings in hepatitis C infection, such as serum HCV-NR (mean, 1.8 in SR, 2.1 in NR; P Å .30), and no specific RNA concentration or responses to interferon. However, variations associated with SR or NR were observed. Although previous studies using a limited number of patients 10 or ana-NR had significantly higher serum levels of pretreatment HCV lyzing a short segment of the 5UTR 11 reported conflicting RNA than SR (median, 16 vs. õ0.5 Meq/mL; P Å .02), there results on the relation between 5UTR variability and rewas no correlation between the HCV-RNA level and the numsponse to interferon. Thus, the actual extent of the IRES ber of nucleotide substitutions in the IRES (mean, 1.9 nucleosequence variability and its clinical significance has not yet tide substitutions in 12 patients with HCV RNA õ0.5 Meq/ been fully elucidated. mL vs. 2.1 nucleotide substitutions in 13 patients with HCV

In the present study, we analyzed the relationship between RNA ú0.5 Meq/mL; P Å .61). Sequence variability of the the nucleotide sequence of the IRES of HCV-1b and serum IRES has no influence on interferon efficacy or serum HCV-HCV-RNA concentrations or responses to interferon to investigate the influence of the IRES sequence variability on clinical findings among patients infected with HCV of the same genotype.