Variability of the Nonstructural 5A Protein of Hepatitis C Virus Type 3a Isolates and Relation to Interferon Sensitivity

• Published in: The Journal of infectious diseases Vol. 185; no. 5; pp. 573 - 583
• Main Authors: Castelain, Sandrine, Khorsi, Hafida, Roussel, Juliette, François, Catherine, Jaillon, Olivier, Capron, Dominique, Penin, François, Wychowski, Czeslaw, Meurs, Eliane, Duverlie, Gilles
• Format: Journal Article
• Language: English
• Published: Chicago, IL The University of Chicago Press 01.03.2002; University of Chicago Press; Oxford University Press
• Subjects: Adult; Amino Acid Sequence; Amino acids; Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; Antivirals; Biochemistry, Molecular Biology; Biological and medical sciences; Drug Resistance, Viral; eIF-2 Kinase - metabolism; Female; Genetic Variation - genetics; Genotypes; Hepacivirus; Hepacivirus - drug effects; Hepatitis C - drug therapy; Hepatitis C - virology; Human viral diseases; Humans; Infectious diseases; Interferon alpha-2; Interferon-alpha - pharmacology; Interferon-alpha - therapeutic use; Interferons; Life Sciences; Major Articles; Male; Medical sciences; Middle Aged; Molecular Sequence Data; Phosphorylation; Proteins; Recombinant Proteins; Sequence Analysis, DNA; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Viral hepatitis; Viral Nonstructural Proteins - chemistry; Viral Nonstructural Proteins - genetics; Viral Nonstructural Proteins - metabolism; Virology; Viruses; Yeasts; Yeast; Double stranded RNA; Growth; Variable region; Hepatic disease; Specificity; Viral hepatitis C; Enzyme; Transferases; Cytokine; Protein; Infection; Virus; Resistance; Sensitivity; Kinase; Protein kinase; Viral disease; Digestive diseases; Isolate; Clinical investigation; Interferon; Flaviviridae; Hepatitis C virus; Hepacivirus
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1086/339051

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.