TY - JOUR
T1 - Genomic response to interferon-α in chimpanzees
T2 - Implications of rapid downregulation for hepatitis C kinetics
AU - Lanford, Robert E.
AU - Guerra, Bernadette
AU - Lee, Helen
AU - Chavez, Deborah
AU - Brasky, Kathleen M.
AU - Bigger, Catherine B.
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2006/5
Y1 - 2006/5
N2 - The mechanism of the interferon-alpha (IFN-α)-induced antiviral response during hepatitis C virus (HCV) therapy is not completely understood. In this study, we examined the transcriptional response to IFN-α in uninfected chimpanzees after single doses of chimpanzee, human, or human-pegylated IFN-α. Liver and peripheral blood mononuclear cell (PBMC) samples were used for total genome microarray analysis. Most induced genes achieved maximal response within 4 hours, began to decline by 8 hours, and were at baseline levels by 24 hours post-inoculation, a time when high levels of circulating pegylated IFN-α were still present. The rapid downregulation of the IFN-α response may be involved in the transition between the observed phase I and phase II viral kinetics during IFN-α therapy in HCV-infected patients. The response to all three forms of IFN-α was similar; thus, the reasons for previous failures in antiviral treatment of chimpanzees with human IFN-α were not due to species specificity of IFN-α. The response to IFN-α was partially tissue-specific. A total of 1,778 genes were altered in expression by twofold or more by IFN-α, with 538 and 950 being unique to the liver or PBMC, respectively. Analysis of the IFN-α and IFN-γ responses in primary chimpanzee and human hepatocytes were compared as well. IFN-α and IFN-γ induced partially overlapping sets of genes in hepatocytes. In conclusion, the response to IFN-α is largely tissue-specific, and the response is rapidly down-regulated in vivo, which may have a significant influence on the kinetics of antiviral response. Supplementary material for this article can be found on the HEPATOLOGY website (http:// interscience.wiley.com/jpages/0270-9139/suppmat/ index.html).
AB - The mechanism of the interferon-alpha (IFN-α)-induced antiviral response during hepatitis C virus (HCV) therapy is not completely understood. In this study, we examined the transcriptional response to IFN-α in uninfected chimpanzees after single doses of chimpanzee, human, or human-pegylated IFN-α. Liver and peripheral blood mononuclear cell (PBMC) samples were used for total genome microarray analysis. Most induced genes achieved maximal response within 4 hours, began to decline by 8 hours, and were at baseline levels by 24 hours post-inoculation, a time when high levels of circulating pegylated IFN-α were still present. The rapid downregulation of the IFN-α response may be involved in the transition between the observed phase I and phase II viral kinetics during IFN-α therapy in HCV-infected patients. The response to all three forms of IFN-α was similar; thus, the reasons for previous failures in antiviral treatment of chimpanzees with human IFN-α were not due to species specificity of IFN-α. The response to IFN-α was partially tissue-specific. A total of 1,778 genes were altered in expression by twofold or more by IFN-α, with 538 and 950 being unique to the liver or PBMC, respectively. Analysis of the IFN-α and IFN-γ responses in primary chimpanzee and human hepatocytes were compared as well. IFN-α and IFN-γ induced partially overlapping sets of genes in hepatocytes. In conclusion, the response to IFN-α is largely tissue-specific, and the response is rapidly down-regulated in vivo, which may have a significant influence on the kinetics of antiviral response. Supplementary material for this article can be found on the HEPATOLOGY website (http:// interscience.wiley.com/jpages/0270-9139/suppmat/ index.html).
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U2 - 10.1002/hep.21167
DO - 10.1002/hep.21167
M3 - Article
C2 - 16628626
AN - SCOPUS:33646573998
VL - 43
SP - 961
EP - 972
JO - Hepatology
JF - Hepatology
SN - 0270-9139
IS - 5
ER -