LA JOLLA, CA—A team led by scientists from Scripps Research and the University of Amsterdam has achieved an important goal in virology: mapping, at high resolution, the critical proteins that stud the surface of the hepatitis C virus (HCV) and allow it to enter host cells.
The finding, reported in Science on October 21, 2022, details the virus’s main sites of vulnerability, sites that can now be effectively targeted with vaccines.
“This long-sought structural information about HCV puts a wealth of previous observations into structural context and paves the way for the rational design of a vaccine against this incredibly challenging target,” says study co-lead author Andrew Ward, PhD, Professor in the Department of Integrative Structural and Computational Biology at Scripps Research.
The study was the product of a multi-year collaboration that included the Ward Lab, the lab of Gabriel Lander, PhD (also a professor in the Department of Integrative Structural and Computational Biology at Scripps Research); the laboratory of Rogier Sanders, PhD, from the University of Amsterdam; and the laboratory of Max Crispin, DPhil, at the University of Southampton.
Approximately 60 million people worldwide, including approximately two million Americans, are expected to suffer from chronic HCV infections. The virus infects liver cells, usually establishing a “silent” infection for decades until liver damage becomes severe enough to cause symptoms. It is one of the main causes of chronic liver disease, liver transplants and primary liver cancer.
The origins of the virus are uncertain, but it is thought to have originated at least several hundred years ago and then eventually spread globally, including through blood transfusions, in the second half of the 20th century. While the virus was largely wiped out from blood banks after its initial discovery in 1989, it continues to spread primarily through needle sharing among intravenous drug users in developed countries and through the use of instruments unsterilized medical supplies in developing countries. The main HCV antiviral drugs are effective but far too expensive for large-scale treatment.
An effective vaccine could eventually eliminate HCV as a public health burden. However, no such vaccine has ever been developed, largely because of the extraordinary difficulty of studying the HCV envelope protein complex, which is made up of two viral proteins called E1 and E2.
“The E1E2 complex is very fragile – it’s like a bag of wet spaghetti, always changing shape – and that’s why it was extremely difficult to image at high resolution,” says co-first author Lisa Eshun- Wilson, PhD, a postdoctoral fellow in Scripps Research’s Lander and Ward Laboratories.
In the study, the researchers found that they could use a combination of three broadly neutralizing anti-HCV antibodies to stabilize the E1E2 complex in a natural conformation. Broadly neutralizing antibodies are those that are able to protect against a wide range of viral strains, by binding to relatively non-variable sites on the virus in such a way as to interrupt the viral life cycle.
The researchers imaged the antibody-stabilized protein complex using low-temperature electron microscopy. With the help of advanced image analysis software, the researchers were able to generate an E1E2 structural map of unprecedented clarity and extent, at near atomic-scale resolution.
The details included most of the structures of the E1 and E2 proteins, including the key E1/E2 interface and the three antibody binding sites. The structural data also shed light on the thicket of sugar-bound “glycan” molecules at the top of E1E2. Viruses often use glycans to protect themselves from an infected host’s immune system, but in this case structural data has shown that HCV glycans apparently have another key role: to help hold the fragile E1E2 complex together.
Having these details about E1E2 will help researchers rationally design a vaccine that potently triggers these antibodies to block HCV infection.
“Structural data should also allow us to uncover the mechanisms by which these antibodies neutralize HCV,” says co-first author Alba Torrents de la Peña, PhD, a postdoctoral researcher in the Ward lab.
“Structure of the Hepatitis C Virus E1E2 Glycoprotein Complex” was co-authored by Alba Torrents de la Peña, Lisa Eshun-Wilson, Gabriel Lander, and Andrew Ward of Scripps Research; Kwinten Sliepen, Ian Zon, Sylvie Koekkoek, Ana Chumbe, Janke Schinkel and Rogier Sanders from the University of Amsterdam; and Maddy Newby, Joel Allen and Max Crispin from the University of Southampton.
Funding was provided by the National Institutes of Health (GM143805, GM142196), the National Science Foundation (2109312), the Netherlands Organization for Scientific Research, the Amsterdam Institute for Infection and Immunity, and the Bill & Melinda Gates Foundation.
About Scripps Research
Scripps Research is an independent, nonprofit biomedical institute ranked the world’s most influential for impact on innovation by the Nature Index. We advance human health through profound discoveries that address pressing medical concerns around the world. Our drug discovery and development division, Calibr, works hand-in-hand with scientists from all disciplines to bring new drugs to patients as quickly and efficiently as possible, while teams at the Scripps Research Translational Institute harness genomics , digital medicine and advanced computing to understand individual health and make healthcare more efficient. Scripps Research also trains the next generation of top scientists at our Skaggs Graduate School, consistently named one of America’s Top 10 Chemistry and Biological Sciences programs. Learn more at www.scripps.edu.