Genomic response to interferon-alpha in chimpanzees: implications of rapid downregulation for hepatitis C kinetics.
The mechanism of the interferon-alpha (IFN-alpha)-induced antiviral response during hepatitis C virus (HCV) therapy is n o t completely understood. In this study,we examined the transcriptional response to IFN-alpha in uninfected chimpanzees after single doses of chimpanzee, human, or human-pegylated IFN-alpha. 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 postinoculation, a time when high levels of circulating pegylated IFN-alpha were still present. The rapid downregulation of the IFN-alpha response may be involved in the transition between the observed phase I and phase II viral kinetics during IFN-alpha therapy in HCV-infected patients. The response to all three forms of IFN-alpha was similar; thus, the reasons for previous failures in antiviral treatment of chimpanzees with human IFN-alpha were not due to species specificity of IFN-alpha. The response to IFN-alpha was partially tissue-specific. A total of 1778 genes were altered in expression by twofold or more by IFN-alpha, with 538 and 950 being unique to the liver or PBMC, respectively. Analysis of the IFN-alpha and IFN-gamma responses in primary chimpanzee and human hepatocytes were compared as well. IFN-alpha and IFN-gamma induced partially overlapping sets of genes in hepatocytes. In conclusion, the response to IFN-alpha is largely tissue-specific, and the response is rapidly downregulated in vivo, which may have a significant influence on the kinetics of antiviral response.
Lanford
Robert E
RE
Department of Virology and Immunology, Southwest Foundation for Biomedical Research, Southwest National Primate Research Center, San Antonio, TX 78227, USA. rlanford@icarus.sfbr.org
Guerra
Bernadette
B
Lee
Helen
H
Chavez
Deborah
D
Brasky
Kathleen M
KM
Bigger
Catherine B
CB
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D015536:Down-Regulation; D016679:Genome, Viral / Q000187:drug effects*; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D002679:Pan troglodytes; D013997:Time Factors
D000998:Antiviral Agents; D016898:Interferon-alpha; D007371:Interferon-gamma