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.
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.
Pawlotsky
J M
JM
Department of Bacteriology and Virology, Hôpital Henri Mondor, Université Paris XII, France.
Hovanessian
A G
AG
Roudot-Thoraval
F
F
Robert
N
N
Bouvier
M
M
Babany
G
G
Duval
J
J
Dhumeaux
D
D
D015088:2',5'-Oligoadenylate Synthetase / Q000096:biosynthesis*; D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology*; D004790:Enzyme Induction; D005260:Female; D006526:Hepatitis C / Q000628:therapy*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology* / Q000627:therapeutic use*; D007527:Isoenzymes; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D011994:Recombinant Proteins; D013997:Time Factors
D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007527:Isoenzymes; D011994:Recombinant Proteins; D015088:2',5'-Oligoadenylate Synthetase