A protein coevolution method uncovers critical features of the Hepatitis C Virus fusion mechanism.

Reference:

PLoS Pathog. 2018 Mar 5;14(3):e1006908. doi: 10.1371/journal.ppat.1006908. [Epub ahead of print]

 

Auteurs:

Douam F1,2,3, Fusil F1, Enguehard M2,4,5, Dib L6, Nadalin F7, Schwaller L8, Hrebikova G3, Mancip J1, Mailly L9,10, Montserret R11, Ding Q3, Maisse C4, Carlot E12, Xu K12, Verhoeyen E1, Baumert TF5,9,10, Ploss A3, Carbone A7,13, Cosset FL1, Lavillette D1,2,4,12.

 

Découvrez l’équipe Virus Enveloppés, Vecteurs et Immunothérapie dirigée par François-Loïc Cosset

 

Résumé:

Amino-acid coevolution can be referred to mutational compensatory patterns preserving the function of a protein. Viral envelope glycoproteins, which mediate entry of enveloped viruses into their host cells, are shaped by coevolution signals that confer to viruses the plasticity to evade neutralizing antibodies without altering viral entry mechanisms. The functions and structures of the two envelope glycoproteins of the Hepatitis C Virus (HCV), E1 and E2, are poorly described. Especially, how these two proteins mediate the HCV fusion process between the viral and the cell membrane remains elusive. Here, as a proof of concept, we aimed to take advantage of an original coevolution method recently developed to shed light on the HCV fusion mechanism. When first applied to the well-characterized Dengue Virus (DENV) envelope glycoproteins, coevolution analysis was able to predict important structural features and rearrangements of these viral protein complexes. When applied to HCV E1E2, computational coevolution analysis predicted that E1 and E2 refold interdependently during fusion through rearrangements of the E2 Back Layer (BL). Consistently, a soluble BL-derived polypeptide inhibited HCV infection of hepatoma cell lines, primary human hepatocytes and humanized liver mice. We showed that this polypeptide specifically inhibited HCV fusogenic rearrangements, hence supporting the critical role of this domain during HCV fusion. By combining coevolution analysis and in vitro assays, we also uncovered functionally-significant coevolving signals between E1 and E2 BL/Stem regions that govern HCV fusion, demonstrating the accuracy of our coevolution predictions. Altogether, our work shed light on important structural features of the HCV fusion mechanism and contributes to advance our functional understanding of this process. This study also provides an important proof of concept that coevolution can be employed to explore viral protein mediated-processes, and can guide the development of innovative translational strategies against challenging human-tropic viruses.

 

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Authors information:

Douam F1,2,3, Fusil F1, Enguehard M2,4,5, Dib L6, Nadalin F7, Schwaller L8, Hrebikova G3, Mancip J1, Mailly L9,10, Montserret R11, Ding Q3, Maisse C4, Carlot E12, Xu K12, Verhoeyen E1, Baumert TF5,9,10, Ploss A3, Carbone A7,13, Cosset FL1, Lavillette D1,2,4,12.

1 CIRI-International Center for Infectiology Research, Team EVIR, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Univ Lyon, Lyon, France.

2 CNRS UMR5557 Microbial ecology, Université Claude Bernard Lyon 1, INRA, UMR1418, Villeurbanne, France.

3 Department of Molecular Biology, Princeton University, Princeton NJ, United States of America.

4 University of Lyon, Université Claude Bernard Lyon1, INRA, EPHE, IVPC, Viral Infections and Comparative Pathology, UMR754, Lyon, France.

5 Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.

6 Molecular Phylogenetics and Speciation, Département d’écologie et évolution, Université de Lausanne, Lausanne, Suisse.

7 Sorbonne Université, CNRS, IBPS, UMR 7238, Laboratoire de Biologie Computationnelle et Quantitative, Paris, France.

8 Mathematical Institute, Leiden University, Leiden, The Netherlands.

9 Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.

10 Université de Strasbourg, Strasbourg, France.

11 Institut de Biologie et Chimie des Protéines, Bases Moléculaires et Structurales des Systèmes Infectieux, Labex Ecofect, UMR 5086 CNRS, Université de Lyon, Lyon, France.

12 CAS Key Laboratory of Molecular Virology and Immunology, Unit of interspecies transmission of arboviruses and antivirals, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

13 Institut Universitaire de France, Paris, France.

 

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