Expression of hepatitis C virus non-structural 5A protein in the liver of transgenic mice

Mainak Majumder, Robert Steele, Asish K. Ghosh, Xiao Yan Zhou, Larry Thornburg, Ranjit Ray, Nancy J. Phillips, Ratna B. Ray

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43 Scopus citations

Abstract

Hepatitis C virus (HCV) is a major etiologic agent for chronic hepatitis worldwide often leading to the development of cirrhosis and hepatocellular carcinoma. However, the mechanism for development of chronic hepatitis or hepatocarcinogenesis by HCV remains unclear. HCV NS5A protein possesses many intriguing properties, including sequestration of p53 in the cytoplasm, downregulation of p21 protein, activation of STAT3, and inhibition of tumor necrosis factor-α-mediated apoptosis. Thus, we investigated whether this viral protein has oncogenic property in vivo. In the absence of an efficient cell culture system for virus growth and a suitable small animal model for HCV infection, transgenic FVB mice were generated by targeting the HCV NS5A genomic region cloned under the control of a liver-specific apoE promoter or mouse major urinary promoter (MUP). The apoE promoter is constitutively expressed in liver, on the other hand, the MUP is developmentally regulated and expressed in the liver after birth. Reverse transcription polymerase chain reaction and Western blot analysis indicated establishment of HCV NS5A transgene expression in several lines from both groups of mice. Immunohistochemical studies suggested the presence of NS5A in the cytoplasm of hepatocytes. The transgenic animals were phenotypically similar to their normal littermates and did not exhibit a major histological change within the liver up to 24 months of age. Our results suggested HCV NS5A protein is not directly cytopathic or oncogenic in this FVB transgenic mouse model, although this viral protein promotes cell growth in vitro. These animals will be a valuable model of HCV immunopathology as well as for evaluation of siRNA, interferon and other cytokine therapies.

Original languageEnglish (US)
Pages (from-to)528-532
Number of pages5
JournalFEBS Letters
Volume555
Issue number3
DOIs
StatePublished - Dec 18 2003

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Keywords

  • Hepatitis C virus
  • Liver specific expression
  • NS5A protein
  • Transgenic mice

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Majumder, M., Steele, R., Ghosh, A. K., Zhou, X. Y., Thornburg, L., Ray, R., Phillips, N. J., & Ray, R. B. (2003). Expression of hepatitis C virus non-structural 5A protein in the liver of transgenic mice. FEBS Letters, 555(3), 528-532. https://doi.org/10.1016/S0014-5793(03)01337-1