HCV causes around 300,000 deaths annually.

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A study published in Nature addresses the impact of chronic hepatitis C virus (HCV) infection, noting that despite its significant health impact, no vaccine is currently available. The virus’s envelope proteins, E1 and E2, form a heterodimer (E1/E2) targeted by neutralizing antibodies. Recent structural analysis has revealed that these E1/E2 heterodimers form a homodimeric structure at the molecular level, providing key insights into the mechanisms of antibody evasion and membrane fusion.

The study detailed the organization of E2 motifs, such as hypervariable region 1 and antigenic site 412, and the arrangement of the transmembrane helices, including two helices internal to E1. This structural information is crucial for understanding how the virus evades immune responses and facilitates membrane fusion.¹

Associate professor Jannick Prentø from the University of Copenhagen highlighted the challenges faced in this research, “Expressing and cleaning up the protein complex is extremely difficult, which is why it has not been done before. The structure of these proteins on the surface of the hepatitis C virus makes them extremely vulnerable. Researchers did not know what they were dealing with, and therefore, whenever someone tried to reproduce these protein structures in the lab they would fall apart before they could get a chance to study them.”²

To overcome these challenges, the researchers used cryo-electron microscopy to determine the structure of the E1/E2 heterodimers in a homodimeric configuration. This method allowed them to visualize the molecular details of homodimer formation and examine the structural organization of the envelope proteins.¹

“We are the first ever to identify the protein complex at the surface of the hepatitis C virus that enables it to bind to our cells,” said associate professor Jannick Prentø.²

Overall, the findings offer valuable insights into HCV’s mechanisms of antibody evasion and membrane fusion. The study addresses long-standing questions about the higher-order organization of E1/E2 heterodimers and provides a critical framework for the design of novel HCV vaccine antigens.

“This knowledge of the structure of the protein complex will enable us to design vaccine candidates that can prevent the virus from infecting the cells,” said Postdoc Elias Augestad.²

References

1. Augestad, E.H., Holmboe Olesen, C., Grønberg, C. et al. The hepatitis C virus envelope protein complex is a dimer of heterodimers. Nature (2024). Accessed September 12, 2024. https://doi.org/10.1038/s41586-024-07783-5

2. We’re closer than ever to solving mystery of deadly virus. EurekAlert. September 9, 2024. Accessed September 12, 2024. https://www.eurekalert.org/news-releases/1057208