Genomic response to interferon-α in chimpanzees:: Implications of rapid downregulation for hepatitis C kinetics

被引:95
作者
Lanford, RE
Guerra, B
Lee, H
Chavez, D
Brasky, KM
Bigger, CB
机构
[1] SW Fdn Biomed Res, SW Natl Primate Res Ctr, Dept Virol & Immunol, San Antonio, TX 78227 USA
[2] SW Fdn Biomed Res, SW Natl Primate Res Ctr, Dept Comparat Med, San Antonio, TX 78227 USA
关键词
D O I
10.1002/hep.21167
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
The mechanism of the interferon-alpha (IFN-alpha)-induced antiviral response during hepatitis C virus (HCV) therapy is not 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-a 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 1,778 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 down-regulated in vivo, which may have a significant influence on the kinetics of antiviral response.
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页码:961 / 972
页数:12
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