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Structure and Assembly

Functional Study of the C-Terminal Part of the Hepatitis C Virus E1 Ectodomain

Rehab I. Moustafa, Juliano G. Haddad, Lydia Linna, Xavier Hanoulle, Véronique Descamps, Ahmed Atef Mesalam, Thomas F. Baumert, Gilles Duverlie, Philip Meuleman, Jean Dubuisson, Muriel Lavie
J.-H. James Ou, Editor
Rehab I. Moustafa
University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019–UMR 8204–CIIL/Centre d'Infection et d'Immunité de Lille, Lille, FranceDepartment of Microbial Biotechnology, Genetic Engineering and Biotechnology Division, National Research Centre, Dokki, Cairo, Egypt
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Juliano G. Haddad
University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019–UMR 8204–CIIL/Centre d'Infection et d'Immunité de Lille, Lille, FranceLaboratoire Microbiologie Santé et Environnement, Ecole Doctorale en Sciences et Technologie, Faculté de Santé Publique, Université Libanaise, Tripoli, Liban
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Lydia Linna
University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019–UMR 8204–CIIL/Centre d'Infection et d'Immunité de Lille, Lille, France
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Xavier Hanoulle
University of Lille, CNRS, UMR 8576, Unité de Glycobiologie Structurale et Fonctionnelle, Lille, France
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Véronique Descamps
Equipe AGIR EA4294, Laboratoire de Virologie du Centre Hospitalier Universitaire d'Amiens, Université de Picardie Jules Verne, Amiens, France
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Ahmed Atef Mesalam
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, BelgiumDepartment of Therapeutic Chemistry, National Research Centre, Dokki, Cairo, EgyptResearch Group Immune- and Bio-markers for Infection, Centre of Excellence for Advanced Sciences, National Research Centre, Dokki, Cairo, Egypt
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Thomas F. Baumert
INSERM, U1110, University of Strasbourg, Pôle Hépato-digestif-Hôpitaux Universitaires de Strasbourg, Strasbourg, France
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Gilles Duverlie
Equipe AGIR EA4294, Laboratoire de Virologie du Centre Hospitalier Universitaire d'Amiens, Université de Picardie Jules Verne, Amiens, France
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Philip Meuleman
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium
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Jean Dubuisson
University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019–UMR 8204–CIIL/Centre d'Infection et d'Immunité de Lille, Lille, France
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Muriel Lavie
University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019–UMR 8204–CIIL/Centre d'Infection et d'Immunité de Lille, Lille, France
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J.-H. James Ou
University of Southern California
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DOI: 10.1128/JVI.00939-18
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ABSTRACT

In the hepatitis C virus (HCV) envelope glycoproteins E1 and E2, which form a heterodimer, E2 is the receptor binding protein and the major target of neutralizing antibodies, whereas the function of E1 remains less characterized. To investigate E1 functions, we generated a series of mutants in the conserved residues of the C-terminal region of the E1 ectodomain in the context of an infectious clone. We focused our analyses on two regions of interest. The first region is located in the middle of the E1 glycoprotein (between amino acid [aa] 270 and aa 291), which contains a conserved hydrophobic sequence and was proposed to constitute a putative fusion peptide. The second series of mutants was generated in the region from aa 314 to aa 342 (the aa314-342 region), which has been shown to contain two α helices (α2 and α3) by nuclear magnetic resonance studies. Of the 22 generated mutants, 20 were either attenuated or noninfectious. Several mutations modulated the virus's dependence on claudin-1 and the scavenger receptor BI coreceptors for entry. Most of the mutations in the putative fusion peptide region affected virus assembly. Conversely, mutations in the α-helix aa 315 to 324 (315-324) residues M318, W320, D321, and M322 resulted in a complete loss of infectivity without any impact on E1E2 folding and on viral assembly. Further characterization of the W320A mutant in the HCVpp model indicated that the loss of infectivity was due to a defect in viral entry. Together, these results support a role for E1 in modulating HCV interaction with its coreceptors and in HCV assembly. They also highlight the involvement of α-helix 315-324 in a late step of HCV entry.

IMPORTANCE HCV is a major public health problem worldwide. The virion harbors two envelope proteins, E1 and E2, which are involved at different steps of the viral life cycle. Whereas E2 has been extensively characterized, the function of E1 remains poorly defined. We characterized here the function of the putative fusion peptide and the region containing α helices of the E1 ectodomain, which had been previously suggested to be important for virus entry. We could confirm the importance of these regions for the virus infectivity. Interestingly, we found several residues modulating the virus's dependence on several HCV receptors, thus highlighting the role of E1 in the interaction of the virus with cellular receptors. Whereas mutations in the putative fusion peptide affected HCV infectivity and morphogenesis, several mutations in the α2-helix region led to a loss of infectivity with no effect on assembly, indicating a role of this region in virus entry.

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Functional Study of the C-Terminal Part of the Hepatitis C Virus E1 Ectodomain
Rehab I. Moustafa, Juliano G. Haddad, Lydia Linna, Xavier Hanoulle, Véronique Descamps, Ahmed Atef Mesalam, Thomas F. Baumert, Gilles Duverlie, Philip Meuleman, Jean Dubuisson, Muriel Lavie
Journal of Virology Sep 2018, 92 (20) e00939-18; DOI: 10.1128/JVI.00939-18

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Functional Study of the C-Terminal Part of the Hepatitis C Virus E1 Ectodomain
Rehab I. Moustafa, Juliano G. Haddad, Lydia Linna, Xavier Hanoulle, Véronique Descamps, Ahmed Atef Mesalam, Thomas F. Baumert, Gilles Duverlie, Philip Meuleman, Jean Dubuisson, Muriel Lavie
Journal of Virology Sep 2018, 92 (20) e00939-18; DOI: 10.1128/JVI.00939-18
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KEYWORDS

hepatitis C virus
glycoprotein
envelope proteins
viral entry
viral assembly

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