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

Abstract

Alpha interferon (IFN-α) 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-α. 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-α. The aim of this study was to determine whether basal and IFN-α-induced in vivo and in vitro 2-5OAS activities measured in peripheral blood mononuclear cells predict biochemical and virological responses to IFN-α in patients with chronic hepatitis C. 2-5OAS activity in peripheral blood mononuclear cells and the antiviral effect of IFN-α 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/106 cells. It was significantly induced at month 3 of IFN-α therapy (18.07 ± 2.74 nmol/106 cells; P = 0.0001). No significant differences were found in basal in vivo 2-5OAS activities, in IFN-α-induced/basal in vitro 2-5OAS activity ratios, in IFN-α-induced in vivo 2-5OAS activities, and in IFN-α-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-α therapy was observed. Our results suggest that a deficiency of the IFN-α-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-α therapy in patients with chronic hepatitis C.