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 prov en efficacy in patients with chronic hepatitis C. However, less than 1 5% of the patients have a sustained response to IFN-alpha, Interferon acts through the induction of various cellular enzymes, Among them, th e 2'-5' oligoadenylate synthetase (2-5OAS) is (at least in part) respo nsible for a direct antiviral effect of IFN-alpha, The aim of this stu dy was to determine whether basal and IFN-alpha-induced in vivo and in vitro 2-5OAS activities measured in peripheral blood mononuclear cell s predict biochemical and virological responses to IFN-alpha in patien ts with chronic hepatitis C. 2-5OAS activity in peripheral blood monon uclear 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 2-5OA S activities, in IFN-alpha-induced/basal in vitro 2-5OAS activity rati os, in IFN-alpha-induced in vivo 2-5OAS activities, and in IFN-alpha-i nduced/basal in vivo 2-5OAS activity ratios between the patients with and without a biochemical response (normal alanine aminotransferase ac tivity in serum) or a virological response (normal alanine aminotransf erase activity in serum and negative hepatitis C virus RNA detection) at any step of the study. At month 3 of therapy, p69, which is conside red to be the active isoform of 2-5OAS, was induced, as demonstrated b y Western blot (immunoblot) analysis in 50% of the patients, and induc tion of the p100 isoform was observed in 70% of the patients, No signi ficant relationship with the response to IFN-alpha therapy,vas observe d, 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 res ponses to IFN-alpha therapy in patients with chronic hepatitis C.