Mutations in the E2-PePHD and NS5A region of hepatitis C virus type 1 and the dynamics of hepatitis C viremia decline during interferon alfa treatment.

Abstract

Both a double-stranded RNA-dependent protein kinase (PKR)-phosphorylation homology domain (PePHD) within the E2 protein and a PKR-binding domain within the nonstructural 5A (NS5A) protein of hepatitis C virus (HCV) genotype 1 isolates inhibit the function of the interferon alfa (IFN-alpha)-induced antiviral effector protein PKR in vitro. We investigated whether the mutational pattern of the E2 region (codons 618-681, including PePHD) of 81 HCV genotype 1-infected patients (HCV-1b [n = 54], HCV-1a [n = 27]) influences the response to IFN-alpha. Initial viral decline (DeltaHCV RNA) was determined at week 1 hereby covering the effector reactions of IFN-alpha-mediated first phase and the immune-mediated second phase. DeltaHCV RNA less than 50% (group 1); DeltaHCV RNA greater than 50% but less than 90% (group 2); and DeltaHCV RNA > or =90% (group 3) were differentiated. The PePHD region was highly conserved; the few mutations (5 patients) did not correlate with DeltaHCV RNA or sustained virologic response to IFN-alpha. Within the flanking regions before and after PePHD (codons 618-681) 72 of 81 patients (89%) had 2.6+/-0.17 mutations (median, 3; range, 1-8) that did not correlate with treatment response. Sequence analysis of the NS5A protein (codons 2,209-2,274, including interferon sensitivity determining region [ISDR]) in 39 of 81 patients showed a higher mean number of mutations in the ISDR (codons 2,209-2,248) in groups 2 (1.28+/- 0.43 [n = 18]) and 3 (1.89+/-0.54 [n = 9]) than in group 1 (0.67+/- 0.19 [n = 12]; P =.049 group 1 vs. 3) and a mutant type ISDR (e.g., > or =4 mutations) was significantly more frequent in sustained virologic responders than in nonresponders or relapsers (2 of 4 [50%] vs. 2 of 35 [6%]; P =.045). Thus, NS5A appears to be functionally relevant in IFN-alpha-induced effector reactions.

• Authors: T Berg, A Mas Marques, M Höhne, B Wiedenmann, U Hopf, E Schreier
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 32 Issue 6 Pg. 1386-95 (Dec 2000) ISSN: 0270-9139 [Print] United States
• PMID: 11093746 (Publication Type: Journal Article)

Chemical References

• Antiviral Agents
• Interferon-alpha
• Peptide Fragments
• Viral Envelope Proteins
• Viral Nonstructural Proteins
• glycoprotein E2, Hepatitis C virus
• eIF-2 Kinase
• NS-5 protein, hepatitis C virus

Topics

• Amino Acid Sequence (genetics)
• Antiviral Agents (therapeutic use)
• Female
• Gene Frequency
• Hepacivirus (genetics, isolation & purification)
• Hepatitis C (drug therapy, virology)
• Humans
• Interferon-alpha (therapeutic use)
• Male
• Middle Aged
• Mutation (genetics)
• Peptide Fragments (genetics)
• Phylogeny
• Protein Structure, Secondary
• Time Factors
• Viral Envelope Proteins (genetics)
• Viral Nonstructural Proteins (genetics, metabolism)
• Viremia (virology)
• eIF-2 Kinase (metabolism)