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Expanding the Host Range of Hepatitis C Virus through Viral Adaptation

Author(s): von Schaewen, Markus; Dorner, Marcus; Hueging, Kathrin; Foquet, Lander; Gerges, Sherif; et al

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Abstract: Hepatitis C virus (HCV) species tropism is incompletely understood. We have previously shown that at the level of entry, human CD81 and occludin (OCLN) comprise the minimal set of human factors needed for viral uptake into murine cells. As an alternative approach to genetic humanization, species barriers can be overcome by adapting HCV to use the murine orthologues of these entry factors. We previously generated a murine tropic HCV (mtHCV or Jc1/mCD81) strain harboring three mutations within the viral envelope proteins that allowed productive entry into mouse cell lines. In this study, we aimed to characterize the ability of mtHCV to enter and infect mouse hepatocytes in vivo and in vitro. Using a highly sensitive, Cre-activatable reporter, we demonstrate that mtHCV can enter mouse hepatocytes in vivo in the absence of any human cofactors. Viral entry still relied on expression of mouse CD81 and SCARB1 and was more efficient when mouse CD81 and OCLN were overexpressed. HCV entry could be significantly reduced in the presence of anti-HCV E2 specific antibodies, suggesting that uptake of mtHCV is dependent on viral glycoproteins. Despite mtHCV’s ability to enter murine hepatocytes in vivo, we did not observe persistent infection, even in animals with severely blunted type I and III interferon signaling and impaired adaptive immune responses. Altogether, these results establish proof of concept that the barriers limiting HCV species tropism can be overcome by viral adaptation. However, additional viral adaptations will likely be needed to increase the robustness of a murine model system for hepatitis C.
Publication Date: Dec-2016
Electronic Publication Date: 8-Nov-2016
Citation: von Schaewen, Markus, Dorner, Marcus, Hueging, Kathrin, Foquet, Lander, Gerges, Sherif, Hrebikova, Gabriela, Heller, Brigitte, Bitzegeio, Julia, Doerrbecker, Juliane, Horwitz, Joshua A, Gerold, Gisa, Suerbaum, Sebastian, Rice, Charles M, Meuleman, Philip, Pietschmann, Thomas, Ploss, Alexander. (2016). Expanding the Host Range of Hepatitis C Virus through Viral Adaptation. mBio, 7 (6), e01915-16 - e01915-16. doi:10.1128/mBio.01915-16
DOI: doi:10.1128/mBio.01915-16
EISSN: 2150-7511
Pages: e01915-16 - e01915-16
Type of Material: Journal Article
Journal/Proceeding Title: mBio
Version: Final published version. This is an open access article.

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