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

Elias Honerød Augestad (), Christina Holmboe Olesen, Christina Grønberg, Andreas Soerensen, Rodrigo Velázquez-Moctezuma, Margherita Fanalista, Jens Bukh, Kaituo Wang (), Pontus Gourdon () and Jannick Prentoe ()
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Elias Honerød Augestad: Copenhagen University Hospital
Christina Holmboe Olesen: Copenhagen University Hospital
Christina Grønberg: University of Copenhagen
Andreas Soerensen: Copenhagen University Hospital
Rodrigo Velázquez-Moctezuma: Copenhagen University Hospital
Margherita Fanalista: Copenhagen University Hospital
Jens Bukh: Copenhagen University Hospital
Kaituo Wang: University of Copenhagen
Pontus Gourdon: University of Copenhagen
Jannick Prentoe: Copenhagen University Hospital

Nature, 2024, vol. 633, issue 8030, 704-709

Abstract: 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 available1. The HCV envelope proteins E1 and E2 form a heterodimer (E1/E2), which is the target for neutralizing antibodies2. 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.

Date: 2024
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DOI: 10.1038/s41586-024-07783-5

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