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 high replication rate, the low fidelity of the RNA-dependent RNA polymerase, and the immune surveillance of the host. Interleukin-12 (IL-12) plays a central role in mounting an effective cellular immune response directed towards elimination of intracellular pathogens. The effect of IL-12 on hepatitis C viremia and the HCV quasispecies population is unknown. In this study, 12 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 microg/kg, 0.1 microg/kg, and 0.5 microg/kg body weight, respectively). Fourteen IFN-alpha non-responders and 14 untreated patients served as age- and sex-matched controls. Serum HCV RNA concentrations and HCV quasispecies distribution were measured serially by quantitative reverse transcription - polymerase chain reaction and single strand conformation polymorphism analysis of the hypervariable region of the second envelope gene, respectively. Serum 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, and 10, respectively). Similar results were observed in 14 IFN-alpha non-responders and 14 untreated patients. However, changes in HCV quasispecies occurred in 10/12 (83%) and 9/14 (64%) patients treated with interleukin-12 and 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 only limited antiviral activity against certain HCV quasispecies in vivo.
Lee
J H
JH
Medizinische Klinik II, Klinikum der Johann Wolfgang Goethe-Universität, D-60590 Frankfurt a.M., Germany.
Teuber
G
G
von Wagner
M
M
Roth
W K
WK
Zeuzem
S
S
D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D016174:Hepacivirus / Q000737:chemistry / Q000187:drug effects* / Q000254:growth & development; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007370:Interferon Type I / Q000627:therapeutic use; D018664:Interleukin-12 / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D018807:Polymorphism, Single-Stranded Conformational; D012367:RNA, Viral / Q000097:blood / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019562:Viral Load
D000998:Antiviral Agents; D007370:Interferon Type I; D012367:RNA, Viral; D011994:Recombinant Proteins; D018664:Interleukin-12