Non-genotype-specific role of the hepatitis C virus 5' untranslated region in virus production and in inhibition by interferon.
The 5' untranslated region (5'UTR) of hepatitis C virus (HCV) is structured into four domains (I-IV) with numerous genotype-specific nucleotides. It is unknown whether the polymorphisms confer genotype-specific functions to the 5'UTR. Using viable JFH1-based Core-NS2 recombinants, we developed and characterized HCV genotypes 1-7 recombinants with highly diverse 5'UTRs (genotypes 1a and 3a), 2a recombinants (J6/JFH1) with 5'UTR of genotypes 1-6 or with heterotypic chimeric (1a/3a and 3a/1a) 5'UTR domains I, II or III, and 1a recombinants with 5'UTR domain I of genotypes 1-6. All were fully functional in Huh7.5 cells; therefore, the 5'UTR apparently functions in a non-genotype-specific manner in HCV production in vitro. However, adenine at the 5'-terminus was required. We demonstrated that J6/JFH1 with 5'UTR of genotypes 1-6 responded similarly to interferon-α2b. This study provides novel insight into the role of the 5'UTR in the HCV life cycle and facilitates HCV basic research and testing of 5'UTR-targeting antivirals.
Copenhagen Hepatitis C Program, Department of Infectious Diseases and Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark.
Yi-Ping
YP
Li
Santseharay
S
Ramirez
Judith M
JM
Gottwein
Jens
J
Bukh
D020121:5' Untranslated Regions; D001483:Base Sequence; D002460:Cell Line; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D012367:RNA, Viral / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D017422:Sequence Analysis, DNA; D014758:Viral Core Proteins / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects* / Q000235:genetics*
D020121:5' Untranslated Regions; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D012367:RNA, Viral; D011994:Recombinant Proteins; D014758:Viral Core Proteins