The hepatitis C virus envelope protein complex is a dimer of heterodimers.

Jens Bukh, Kaituo Wang, Christina Grønberg, Pontus Gourdon, Elias Honerød Augestad, Christina Holmboe Olesen, Andreas Soerensen, Rodrigo Velázquez-Moctezuma, Margherita Fanalista, Jannick Prentoe

Journal: Nature 2024;633(8030):704-709

PMID: 39232163

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Abstract

Fifty-eight million individuals worldwide are affected by chronic hepatitis C virus (HCV) infection, a primary driver of liver cancer for which no vaccine is available. The HCV envelope proteins E1 and E2 form a heterodimer (E1/E2), which is the target for neutralizing antibodies. However, the higher-order organization of these E1/E2 heterodimers, as well as that of any Hepacivirus envelope protein complex, remains unknown. Here we determined the cryo-electron microscopy structure of two E1/E2 heterodimers in a homodimeric arrangement. We reveal how the homodimer is established at the molecular level and provide insights into neutralizing antibody evasion and membrane fusion by HCV, as orchestrated by E2 motifs such as hypervariable region 1 and antigenic site 412, as well as the organization of the transmembrane helices, including two internal to E1. This study addresses long-standing questions on the higher-order oligomeric arrangement of Hepacivirus envelope proteins and provides a critical framework in the design of novel HCV vaccine antigens.

Address: Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Denmark. [email protected].; Copenhagen Hepatitis C Program (CO-HEP), Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. [email protected].; Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Denmark.; Copenhagen Hepatitis C Program (CO-HEP), Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. [email protected].; State Key Laboratory of Plant Diversity and Specialty Crops, Institute of Botany, Chinese Academy of Sciences, Beijing, China. [email protected].; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. [email protected].; Department of Experimental Medical Science, Faculty of Medicine, Lund University, Lund, Sweden. [email protected].; Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Denmark. [email protected].; Copenhagen Hepatitis C Program (CO-HEP), Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. [email protected].

DOI: 10.1038/s41586-024-07783-5

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MeSH Terms: Humans, Amino Acid Motifs, Antibodies, Neutralizing, Cryoelectron Microscopy, Hepacivirus, Immune Evasion, Membrane Fusion, Models, Molecular, Protein Multimerization, Viral Envelope Proteins, Virus Internalization, Viral Hepatitis Vaccines