Intrahepatic Transcriptional Signature Associated with Response to Interferon-α Treatment in the Woodchuck Model of Chronic Hepatitis B.
Recombinant interferon-alpha (IFN-α) is an approved therapy for chronic hepatitis B (CHB), but the molecular basis of treatment response remains to be determined. The woodchuck model of chronic hepatitis B virus (HBV) infection displays many characteristics of human disease and has been extensively used to evaluate antiviral therapeutics. In this study, woodchucks with chronic woodchuck hepatitis virus (WHV) infection were treated with recombinant woodchuck IFN-α (wIFN-α) or placebo (n = 12/group) for 15 weeks. Treatment with wIFN-α strongly reduced viral markers in the serum and liver in a subset of animals, with viral rebound typically being observed following cessation of treatment. To define the intrahepatic cellular and molecular characteristics of the antiviral response to wIFN-α, we characterized the transcriptional profiles of liver biopsies taken from animals (n = 8-12/group) at various times during the study. Unexpectedly, this revealed that the antiviral response to treatment did not correlate with intrahepatic induction of the majority of IFN-stimulated genes (ISGs) by wIFN-α. Instead, treatment response was associated with the induction of an NK/T cell signature in the liver, as well as an intrahepatic IFN-γ transcriptional response and elevation of liver injury biomarkers. Collectively, these data suggest that NK/T cell cytolytic and non-cytolytic mechanisms mediate the antiviral response to wIFN-α treatment. In summary, by studying recombinant IFN-α in a fully immunocompetent animal model of CHB, we determined that the immunomodulatory effects, but not the direct antiviral activity, of this pleiotropic cytokine are most closely correlated with treatment response. This has important implications for the rational design of new therapeutics for the treatment of CHB.
Pharma Research & Early Development, Hoffmann-La Roche, Inc., Nutley, New Jersey, United States of America.
Simon P
SP
Fletcher
Pharma Research & Early Development, Hoffmann-La Roche, Inc., Nutley, New Jersey, United States of America.
Daniel J
DJ
Chin
Pharma Research & Early Development, Hoffmann-La Roche, Inc., Nutley, New Jersey, United States of America.
Lore
L
Gruenbaum
Pharma Research & Early Development, Hoffmann-La Roche, Inc., Nutley, New Jersey, United States of America.
Hans
H
Bitter
Pharma Research & Early Development, Hoffmann-La Roche, Inc., Nutley, New Jersey, United States of America.
Erik
E
Rasmussen
Pharma Research & Early Development, Hoffmann-La Roche, Inc., Nutley, New Jersey, United States of America.
Palanikumar
P
Ravindran
Pharma Research & Early Development, Hoffmann-La Roche, Inc., Nutley, New Jersey, United States of America.
David C
DC
Swinney
Roche Pharma Research & Early Development, Roche Innovation Center Penzberg, Penzberg, Germany.
Fabian
F
Birzele
Roche Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland.
Roland
R
Schmucki
Roche Pharma Research & Early Development, Roche Innovation Center Penzberg, Penzberg, Germany.
Stefan H
SH
Lorenz
Roche Pharma Research & Early Development, Roche Innovation Center Penzberg, Penzberg, Germany.
Erhard
E
Kopetzki
Pharma Research & Early Development, Hoffmann-La Roche, Inc., Nutley, New Jersey, United States of America.
Jade
J
Carter
Roche Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland.
Miriam
M
Triyatni
Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, District of Columbia, United States of America.
Linta M
LM
Thampi
Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, District of Columbia, United States of America.
Junming
J
Yang
Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, District of Columbia, United States of America.
Dalal
D
AlDeghaither
Marta G
MG
Murreddu
Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, District of Columbia, United States of America.
Marta G
MG
Murredu
Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, District of Columbia, United States of America.
Paul
P
Cote
Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, District of Columbia, United States of America.
Stephan
S
Menne
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D001706:Biopsy; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D017919:Hepatitis B Virus, Woodchuck / Q000187:drug effects / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000188:drug therapy / Q000378:metabolism / Q000662:veterinary* / Q000821:virology; D007111:Immunity, Cellular / Q000187:drug effects*; D007155:Immunologic Factors / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D016898:Interferon-alpha / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D008297:Male; D008392:Marmota; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic; D019562:Viral Load / Q000187:drug effects
D000998:Antiviral Agents; D015415:Biomarkers; D007155:Immunologic Factors; D016898:Interferon-alpha; D011994:Recombinant Proteins