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Effect of alpha interferon (IFN-alpha) on 2'-5' oligoadenylate synthetase activity in peripheral blood mononuclear cells of patients with chronic hepatitis C: relationship to the antiviral effect of IFN-alpha.

Abstract
Alpha interferon (IFN-alpha) is, to date, the only treatment with proven efficacy in patients with chronic hepatitis C. However, less than 15% of the patients have a sustained response to IFN-alpha. Interferon acts through the induction of various cellular enzymes. Among them, the 2'-5' oligoadenylate synthetase (2-5OAS) is (at least in part) responsible for a direct antiviral effect of IFN-alpha. The aim of this study was to determine whether basal and IFN-alpha-induced in vivo and in vitro 2-5OAS activities measured in peripheral blood mononuclear cells predict biochemical and virological responses to IFN-alpha in patients with chronic hepatitis C. 2-5OAS activity in peripheral blood mononuclear cells and the antiviral effect of IFN-alpha were studied in 36 patients with chronic hepatitis C (27 men and 9 women; mean age, 44.7 years). Basal in vivo 2-5OAS activity (mean +/- standard error of the mean) was 4.41 +/- 0.69 nmol/10(6) cells. It was significantly induced at month 3 of IFN-alpha therapy (18.07 +/- 2.74 nmol/10(6) cells; P = 0.0001). No significant differences were found in basal in vivo 2-5OAS activities, in IFN-alpha-induced/basal in vitro 2-5OAS activity ratios, in IFN-alpha-induced in vivo 2-5OAS activities, and in IFN-alpha-induced/basal in vivo 2-5OAS activity ratios between the patients with and without a biochemical response (normal alanine aminotransferase activity in serum) or a virological response (normal alanine aminotransferase activity in serum and negative hepatitis C virus RNA detection) at any step of the study. At month 3 of therapy, p69, which is considered to be the active isoform of 2-5OAS, was induced, as demonstrated by Western blot (immunoblot) analysis in 50% of the patients, and induction of the p100 isoform was observed in 70% of the patients. No significant relationship with the response to IFN-alpha therapy was observed. Our results suggest that a deficiency of the IFN-alpha-dependent 2-5OAS system, which could be genetically determined, is unlikely to be responsible for the failure to achieve biochemical and virological responses to IFN-alpha therapy in patients with chronic hepatitis C.
AuthorsJ M Pawlotsky, A G Hovanessian, F Roudot-Thoraval, N Robert, M Bouvier, G Babany, J Duval, D Dhumeaux
JournalAntimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 40 Issue 2 Pg. 320-4 (Feb 1996) ISSN: 0066-4804 [Print] UNITED STATES
PMID8834873 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antiviral Agents
  • Interferon-alpha
  • Isoenzymes
  • Recombinant Proteins
  • interferon alfa-2a
  • 2',5'-Oligoadenylate Synthetase
Topics
  • 2',5'-Oligoadenylate Synthetase (biosynthesis)
  • Adult
  • Antiviral Agents (pharmacology)
  • Enzyme Induction
  • Female
  • Hepatitis C (therapy)
  • Humans
  • Interferon-alpha (pharmacology, therapeutic use)
  • Isoenzymes
  • Leukocytes, Mononuclear (drug effects, enzymology)
  • Male
  • Microbial Sensitivity Tests
  • Middle Aged
  • Recombinant Proteins
  • Time Factors

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