Variability of the nonstructural 5A protein of hepatitis C virus type 3a isolates and relation to interferon sensitivity.
The nonstructural 5A (NS5A) protein of hepatitis C virus (HCV) genotype 1 is thought to interact with several cellular proteins, including the double-stranded RNA-dependent protein kinase (PKR) induced by interferon (IFN). The PKR-binding domain (PKR-BD; aa 2209-2274), including the IFN sensitivity-determining region (aa 2209-2248) and other regions, could be linked to IFN resistance. Thus, the entire NS5A sequence of 27 isolates of HCV genotype 3a was investigated in relation to the clinical response to IFN. The NS5A 3a protein presented a low variability with some specific variable regions. Differential analysis between IFN-resistant and -sensitive isolates identified 5 regions in NS5A, 2 of them inside the PKR-BD and another around the variable 3 region. However, using the yeast growth suppression assay, no interaction was found between 5 resistant NS5A 3a proteins and PKR. Some amino acid changes of the NS5A protein of genotype 3a seemed to relate to IFN resistance independently of the PKR pathway.
Castelain
Sandrine
S
Laboratoire de Virologie, Centre Hospitalo Universitaire, 80054 Amiens Cedex, France. sandrine.castelain@u-picardie.fr
Khorsi
Hafida
H
Roussel
Juliette
J
François
Catherine
C
Jaillon
Olivier
O
Capron
Dominique
D
Penin
François
F
Wychowski
Czeslaw
C
Meurs
Eliane
E
Duverlie
Gilles
G
D000328:Adult; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D024882:Drug Resistance, Viral; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D011994:Recombinant Proteins; D017422:Sequence Analysis, DNA; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D017361:Viral Nonstructural Proteins; D019892:eIF-2 Kinase; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase