Mice expressing minimally humanized CD81 and occludin genes support hepatitis C virus uptake in vivo

Qiang Ding, Markus von Schaewen, Gabriela Hrebikova, Brigitte Heller, Lisa Sandmann, Mario Plaas, Alexander Ploss

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Hepatitis C virus (HCV) causes chronic infections in at least 150 million individuals worldwide. HCV has a narrow host range and robustly infects only humans and chimpanzees. The underlying mechanisms for this narrow host range are incompletely understood. At the level of entry, differences in the amino acid sequences between the human and mouse orthologues of two essential host factors, the tetraspanin CD81 and the tight junction protein occludin (OCLN), explain, at least in part, HCV's limited ability to enter mouse hepatocytes. We have previously shown that adenoviral or transgenic overexpression of human CD81 and OCLN facilitates HCV uptake into mouse hepatocytes in vitro and in vivo. In efforts to refine these models, we constructed knock-in mice in which the second extracellular loops of CD81 and OCLN were replaced with the respective human sequences, which contain the determinants that are critical for HCV uptake. We demonstrate that the humanized CD81 and OCLN were expressed at physiological levels in a tissue-appropriate fashion. Mice bearing the humanized alleles formed normal tight junctions and did not exhibit any immunologic abnormalities, indicating that interactions with their physiological ligands were intact. HCV entry factor knock-in mice take up HCV with an efficiency similar to that in mice expressing HCV entry factors transgenically or adenovirally, demonstrating the utility of this model for studying HCV infection in vivo.

Original languageEnglish (US)
Article numbere01799-16
JournalJournal of virology
Volume91
Issue number4
DOIs
StatePublished - 2017

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Keywords

  • Animal models
  • Hepatitis C virus
  • Viral entry
  • Viral hepatitis

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