A team of researchers from Scripps Research and the University of Amsterdam have learned how to map high-resolution images of critical proteins on the surface of the Hepatitis C virus.
The new discovery is an important achievement in the study of virology as it enables scientists to enter the host cells. A report has been published in the journal Science, detailing the key sites of vulnerability in the Hepatitis C virus. It is hoped the research will allow effective targeting of these areas through vaccination.
“This long sought-after structural information on HCV puts a wealth of previous observations into a structural context and paves the way for rational vaccine design against this incredibly difficult target,” said study co-senior author Andrew Ward, PhD, professor in the Department of Integrative Structural and Computational Biology at Scripps Research.
Hepatitis C virus imaging could prevent cancer and liver disease
It is estimated that 60 million people across the world have chronic Hepatitis C virus infections. Hepatitis C virus-infected cells in the liver, and the disease can remain ‘silent’ for several decades until the liver damage becomes severe enough to become symptomatic. The Hepatitis C virus is a leading cause of chronic liver disease, liver transplants, and liver cancer.
The virus, which was often spread through blood transfusions, has been mostly eliminated from blood banks. However, the virus is still widely spread via need-sharing among drug users in developed in countries. In developing countries, the Hepatitis C virus is often spread through unsterilised medical instruments. Leading antiviral drugs are effective against the Hepatitis C virus but are too expensive for large-scale administration.
Through an effective vaccine, Hepatitis C could be eliminated as a public health burden. No such vaccine has been developed; this is due to the difficulty in studying the virus’s envelope protein complex. This complex is made of two viral proteins called E1 and E2.
“The E1E2 complex is very flimsy—it’s like a bag of wet spaghetti, always changing its shape—and that’s why it’s been extremely challenging to image at high resolution,” explained co-first author Lisa Eshun-Wilson, PhD, a postdoctoral research associate in both the Lander and Ward labs at Scripps Research.
The researchers used a combination of three broadly neutralising anti-Hepatitis antibodies to stabilise the E1E2 complex in a natural conformation. Broadly neutralising antibodies can protect against a range of viral strains. They do this by binding to non-varying sites on the virus, interrupting the viral life cycle.
Unprecedented levels of viral imaging
The researchers then imaged the antibody-stabilised protein complex using low-temperature electron microscopy. Using advanced image-analysis software, the researchers generated an E1E2 structural map of unprecedented clarity.
These images illuminated several key structural findings of the E1 and E2 proteins, including structural data on the sugar-related glycan molecules atop the proteins. Viruses use glycans to protect themselves from the body’s immune system. This new data has shown that the Hepatitis C virus glycans also help to hold the E1E2 complex together.
The findings could help researchers design a vaccine that elicits these antibodies to block Hepatitis infection.
“The structural data also should allow us to discover the mechanisms by which these antibodies neutralise the virus,” said co-first author Alba Torrents de la Peña, PhD, a postdoctoral researcher in the Ward lab.
