Most people infected by the hepatitis C virus (HCV) can be cured with antiviral therapy, but access to the treatment remains limited. Even diagnosis of hepatitis C, a disease that causes chronic inflammation in 58 million people, remains a challenge. An effective vaccine is needed, but currently, none exists.
Unfortunately, developing a hepatitis C vaccine has been difficult because little is known about the protein complex that enables the virus to infect host cells. Although the hepatitis C virus’s envelope proteins E1 and E2 are known to form a heterodimer (E1/E2) that is a target for neutralizing antibodies, the higher-order organization of these E1/E2 heterodimers, as well as that of any Hepacivirus envelope protein complex, remains unknown
To determine the structure of the E1/E2 protein complex—and thereby inform vaccine development efforts—a cross-disciplinary research team at the University of Copenhagen made use of cyro-electron microscopy. Ultimately, the researchers determined the structure of two E1/E2 heterodimers in a homodimeric arrangement.
Detailed findings appeared in Nature, in an article titled, “The hepatitis C virus envelope protein complex is a dimer of heterodimers.”
“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,” the article’s authors reported. “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.”
One of the article’s senior authors, associate professor Jannick Prentø, stated, “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.”
“This knowledge will enable us to design vaccine candidates that can prevent the virus from infecting the cells,” added one of the article’s lead authors, postdoctoral researcher Elias Augestad, PhD.
The protein complex helps the virus bind to the cells. In the coronavirus, it is a so-called spike protein with the well-known spikes. In the hepatitis C virus, the structure is different, but the function of the protein complex is the same.
The study can be considered a blueprint for HCV vaccine development. Scientists hope to be able to use the new knowledge to develop a vaccine that will make the immune system produce antibodies that bind effectively to the surface of the hepatitis C virus and thus render it harmless.
“Expressing and cleaning up the protein complex is extremely difficult, which is why it has not been done before,” Prentø noted. “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.”
Nonetheless, the research team managed to describe their structure, noted another of the article’s senior authors, associate professor Pontus Gourdon. He observed, “This has enabled us to reproduce these protein complexes outside the cell and study them closely.”
