Adaptation of hepatitis C virus to mouse CD81 permits infection of mouse cells in the absence of human entry factors.

2.50
Hdl Handle:
http://hdl.handle.net/10033/550486
Title:
Adaptation of hepatitis C virus to mouse CD81 permits infection of mouse cells in the absence of human entry factors.
Authors:
Bitzegeio, Julia; Bankwitz, Dorothea; Hueging, Kathrin; Haid, Sibylle; Brohm, Christiane; Zeisel, Mirjam B; Herrmann, Eva; Iken, Marcus; Ott, Michael; Baumert, Thomas F; Pietschmann, Thomas
Abstract:
Hepatitis C virus (HCV) naturally infects only humans and chimpanzees. The determinants responsible for this narrow species tropism are not well defined. Virus cell entry involves human scavenger receptor class B type I (SR-BI), CD81, claudin-1 and occludin. Among these, at least CD81 and occludin are utilized in a highly species-specific fashion, thus contributing to the narrow host range of HCV. We adapted HCV to mouse CD81 and identified three envelope glycoprotein mutations which together enhance infection of cells with mouse or other rodent receptors approximately 100-fold. These mutations enhanced interaction with human CD81 and increased exposure of the binding site for CD81 on the surface of virus particles. These changes were accompanied by augmented susceptibility of adapted HCV to neutralization by E2-specific antibodies indicative of major conformational changes of virus-resident E1/E2-complexes. Neutralization with CD81, SR-BI- and claudin-1-specific antibodies and knock down of occludin expression by siRNAs indicate that the adapted virus remains dependent on these host factors but apparently utilizes CD81, SR-BI and occludin with increased efficiency. Importantly, adapted E1/E2 complexes mediate HCV cell entry into mouse cells in the absence of human entry factors. These results further our knowledge of HCV receptor interactions and indicate that three glycoprotein mutations are sufficient to overcome the species-specific restriction of HCV cell entry into mouse cells. Moreover, these findings should contribute to the development of an immunocompetent small animal model fully permissive to HCV.
Citation:
Adaptation of hepatitis C virus to mouse CD81 permits infection of mouse cells in the absence of human entry factors. 2010, 6:e1000978 PLoS Pathog.
Journal:
PLoS pathogens
Issue Date:
2010
URI:
http://hdl.handle.net/10033/550486
DOI:
10.1371/journal.ppat.1000978
PubMed ID:
20617177
Type:
Article
Language:
en
ISSN:
1553-7374
Appears in Collections:
publications of the department experimental Virology([TC]EVIR)

Full metadata record

DC FieldValue Language
dc.contributor.authorBitzegeio, Juliaen
dc.contributor.authorBankwitz, Dorotheaen
dc.contributor.authorHueging, Kathrinen
dc.contributor.authorHaid, Sibylleen
dc.contributor.authorBrohm, Christianeen
dc.contributor.authorZeisel, Mirjam Ben
dc.contributor.authorHerrmann, Evaen
dc.contributor.authorIken, Marcusen
dc.contributor.authorOtt, Michaelen
dc.contributor.authorBaumert, Thomas Fen
dc.contributor.authorPietschmann, Thomasen
dc.date.accessioned2015-04-23T08:12:48Zen
dc.date.available2015-04-23T08:12:48Zen
dc.date.issued2010en
dc.identifier.citationAdaptation of hepatitis C virus to mouse CD81 permits infection of mouse cells in the absence of human entry factors. 2010, 6:e1000978 PLoS Pathog.en
dc.identifier.issn1553-7374en
dc.identifier.pmid20617177en
dc.identifier.doi10.1371/journal.ppat.1000978en
dc.identifier.urihttp://hdl.handle.net/10033/550486en
dc.description.abstractHepatitis C virus (HCV) naturally infects only humans and chimpanzees. The determinants responsible for this narrow species tropism are not well defined. Virus cell entry involves human scavenger receptor class B type I (SR-BI), CD81, claudin-1 and occludin. Among these, at least CD81 and occludin are utilized in a highly species-specific fashion, thus contributing to the narrow host range of HCV. We adapted HCV to mouse CD81 and identified three envelope glycoprotein mutations which together enhance infection of cells with mouse or other rodent receptors approximately 100-fold. These mutations enhanced interaction with human CD81 and increased exposure of the binding site for CD81 on the surface of virus particles. These changes were accompanied by augmented susceptibility of adapted HCV to neutralization by E2-specific antibodies indicative of major conformational changes of virus-resident E1/E2-complexes. Neutralization with CD81, SR-BI- and claudin-1-specific antibodies and knock down of occludin expression by siRNAs indicate that the adapted virus remains dependent on these host factors but apparently utilizes CD81, SR-BI and occludin with increased efficiency. Importantly, adapted E1/E2 complexes mediate HCV cell entry into mouse cells in the absence of human entry factors. These results further our knowledge of HCV receptor interactions and indicate that three glycoprotein mutations are sufficient to overcome the species-specific restriction of HCV cell entry into mouse cells. Moreover, these findings should contribute to the development of an immunocompetent small animal model fully permissive to HCV.en
dc.language.isoenen
dc.subject.meshAnimalsen
dc.subject.meshAntigens, CDen
dc.subject.meshAntigens, CD81en
dc.subject.meshClaudin-1en
dc.subject.meshHepacivirusen
dc.subject.meshMembrane Proteinsen
dc.subject.meshMiceen
dc.subject.meshReceptors, Virusen
dc.subject.meshScavenger Receptors, Class Ben
dc.subject.meshViral Envelope Proteinsen
dc.subject.meshVirus Internalizationen
dc.titleAdaptation of hepatitis C virus to mouse CD81 permits infection of mouse cells in the absence of human entry factors.en
dc.typeArticleen
dc.identifier.journalPLoS pathogensen

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