Antiviral effect of human recombinant interleukin-12 in patients infected with hepatitis C virus

The heterogeneity of hepatitis C virus (HCV) is due to the continuous and h igh replication rate, the low fidelity of the RNA-dependent RNA polymerase, and the immune surveillance of the host. Interleukin-12 (IL-12) plays a ce ntral role in mounting an effective cellular immune response directed towar ds elimination of intracellular pathogens. The effect of IL-12 on hepatitis C viremia and the HCV quasispecies population is unknown. In this study, 1 2 patients (9 males, 3 females; mean age: 44 +/- 11 years), all virological non-responders to previous IFN-alpha treatment, received recombinant human IL-12 s.c. once weekly for 10 weeks stratified to three dose schedules (0. 03 mu g/ikg, 0.1 mu g/kg, and 0.5 mu g/kg body weight, respectively). Fourt een IFN-alpha nonresponders and 14 untreated patients served as age- and se x-matched controls. Serum HCV RNA concentrations and HCV quasispecies distr ibution were measured serially by quantitative reverse transcription - poly merase chain reaction and single strand conformation polymorphism analysis of the hypervariable region of the second envelope gene, respectively. Seru m ALT and median HCV RNA levels before treatment (52.7 +/- 21.7 U/L; 2.6 x 10(6) copies/mL) showed no significant changes during IL-12 treatment (57.3 +/- 58.8 U/L and 3.2 x 10(6) copies/mL, 50.3 +/- 46.2 U/L and 3.1 x 10(6) copies/mL, and 46.8 +/- 35.3 U/L and 3.9 x 10(6) copies/mL at weeks 1, 4, a nd 10, respectively). Similar results were observed in 14 IFN-alpha non-res ponders and 14 untreated patients. However, changes in HCV quasispecies occ urred in 10/12 (83%) and 9/14 (64%) patients treated with interleukin-12 an d interferon-alpha, respectively, but only in 3/14 (21%) untreated subjects (P< 0.003 and P< 0.03). These results imply that interleukin-12 exerts onl y limited antiviral activity against certain HCV quasispecies in vivo. J. M ed. Virol 60:264-268, 2000. (C) 2000 Wiley-Liss, Inc.