Important protein structure of hepatitis C virus

A team led by scientists at the Scripps Institute and the University of Amsterdam has achieved an important goal in virology: mapping in high resolution key proteins
that attach to the surface of the hepatitis C virus (HCV) and enable it to enter host cells.

The findings, published in the journal Science on October 21, 2022, detail the key vulnerable sites of the virus that can now be effectively targeted with
vaccines.

Dr.
Gabriel Lander, a professor in the Scripps Research Institute's Department of Integrated Structural and Computational Biology and senior co-author of the study, said: "This long-tracted HCV structural information incorporates a large number of previous observations into the structural context, paving the way
for rational vaccine design for this incredible goal.
"

The research is the product of years of collaboration, which includes Ward's lab, Dr.
Gabriel Lander's lab (also a professor in the Scripps Research Institute's Department of Integrated Structural and Computational Biology); the laboratory of Dr.
Rogier Sanders, University of Amsterdam; and Max Crispin's lab
at the University of Southampton.

It is estimated that about 60 million people worldwide – including about 2 million Americans – have chronic hepatitis C virus infection
.
This virus infects liver cells, often forming a "silent" infection over decades until the liver damage is severe enough to cause symptoms
.
It is the leading cause of
chronic liver disease, liver transplantation, and primary liver cancer.

The origin of the virus is uncertain, but it is thought to have appeared at least a few hundred years ago and eventually spread
globally through blood transfusions in the second half of the 20th century.
Although the virus has been largely eliminated from blood banks since it was first detected in 1989, it continues to spread
mainly through the sharing of needles among intravenous drug users in developed countries and the use of unsterilized medical devices in developing countries.
The main antiviral drugs for hepatitis C are effective, but too expensive
for large-scale treatment.

An effective vaccine may eventually eliminate HCV as a public health burden
.
However, no such vaccine has been developed so far — mainly because it is very difficult to study the envelope protein complex of the hepatitis C virus, which consists of
two viral proteins, E1 and E2.

"The E1E2 composite structure is very fragile – it's like a bag of wet pasta, always changing shape – which is why imaging at high resolution is very challenging," said
co-first author Dr.
Lisa Eshun-Wilson.

In this study, the researchers found that they could use a combination of three broadly neutralizing anti-HCV antibodies to stabilize the natural conformation of the E1E2 complex
.
Broadly neutralizing antibodies are those that protect themselves from multiple virus strains by binding to relatively unchanged sites on the virus in a way that
interrupts the life cycle of the virus.

The researchers used cryo-electron microscopy to image
the antibody stabilized protein complex.
With the help of advanced image analysis software, researchers were able to generate E1E2 structure maps with near-atomic resolution with unprecedented
clarity and breadth.

Details include most E1 and E2 protein structures, including key E1/E2 interfaces, and three antibody binding sites
.
Structural data also revealed sugar-related "glycan" molecules
on top of E1E2.
Viruses typically use glycans to protect themselves from the immune system of an infected host, but in this case, structural data shows that the glycans of the hepatitis C virus clearly have another key role: helping to hold the fragile E1E2 complex together
.
Understanding these details of E1E2 will help researchers rationally design a vaccine that can strongly stimulate these antibodies to stop HCV infection
.

Alba Torrents de la Peñ a, Kwinten Sliepen, Lisa Eshun-Wilson, Maddy L.
Newby, Joel D.
Allen, Ian Zon, Sylvie Koekkoek, Ana Chumbe, Max Crispin, Janke Schinkel, Gabriel C.
Lander, Rogier W.
Sanders, Andrew B.
Ward.
Structure of the hepatitis C virus E1E2 glycoprotein complex.
Science, 2022; 378 (6617): 263