Scientists discover Hepatitis C virus critical protein structure.
It is estimated that around 60 million people worldwide suffer from chronic HCV-related infections. The virus infects the liver cells, causing the condition of a “silent” infection for decades until liver damage is sufficient to trigger symptoms.
A team of scientists from Scripps Research and the University of Amsterdam is achieving an important goal in the field of virology that is mapping, with high resolution, the critical proteins that examine the surface of Hepatitis C virus (HCV) and allow the virus to enter the host cell.
The research, published in Science on 21 October 2022, provides the key areas of vulnerability to the virus sites that can be targeted using vaccines.
“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,” says co-author of the study Andrew Ward, PhD, professor of the Department of Integrative Structural and Computational Biology at Scripps Research.
The research was the result of a multi-year partnership which included the Ward lab, as well as the laboratory of Gabriel Lander, PhD (also an instructor of the Department of Integrative Structural and Computational Biology at Scripps Research); the laboratory that is run by Rogier Sanders, Ph.D from the University of Amsterdam; and the lab of Max Crispin, DPhil, at the University of Southampton.
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It is estimated that around 60 million people worldwide which includes around two million Americans are suffering from chronic HCV illnesses. The virus affects the liver cells, and typically causes an “silent” infection for decades until the damage to the liver is severe enough to trigger symptoms. It is a major reason for chronic liver diseases, transplants, and primary liver cancers.
Scientists map Hepatitis C virus’ critical protein structure https://t.co/VoK7OarCDH
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The nature of the virus is not clear, but it is believed that it occurred at least a hundred years ago. It it then spread to the entire world -particularly through blood transfusions during the second half in the second half of 20th century.
Although the virus was largely removed from blood banks following the initial detection in the year 1989, it is still grow through the sharing of needles with intravenous drug users within advanced countries, as well as via the use of non-sterilized medical devices in countries that are less developed. The most effective HCV antiviral drugs work however they are expensive for widespread treatment.
A successful vaccine may eventually eradicate HCV as a health risk. But, no vaccine has been ever developed mostly due to the incredibly difficult task of understanding the HCV envelope protein complex composed of two viral proteins known as E1 as well as 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,” says co-first author Lisa Eshun Wilson, PhD, postdoctoral research associate with both Lander as well as the Ward Labs of Scripps Research.
The study researchers discovered that they can make use of a mixture of three anti-HCV antibodies that neutralize HCV for stabilizing the E1E2 complex in its natural form. Widely neutralizing antibody are ones capable of protecting against a variety of virus strains by binding to generally non-changing areas that are found on this virus, in ways to stop the life cycle of viral infection.
The researchers examined the protein-stabilized antibody complex using electron microscopy at low temperatures. With the aid of sophisticated image analysis software, the researchers were able create the E1E2 structural map that was unimaginably clarity and size with near-atomic resolution.
The details covered the majority of E1 and E2 proteins, as well as the crucial E1/E2 interface as well as the three binding sites to antibodies. The structural analysis also highlighted the quantity of related sugar “glycan” molecules atop E1E2. Viruses typically use glycans in order to protect their immune systems from the host, however in this case, analysis of the structural data indicated that the glycans of HCV have an additional function: helping to keep the fragile E1E2 complex.
Knowing the details of E1E2 will allow researchers to develop a vaccine that effectively induces these antibodies and blocks HCV infection.
“The structural data also should allow us to discover the mechanisms by which these antibodies neutralize HCV,” says co-first author Alba Torrents de la Pena PhD, postdoctoral researcher at the Ward Lab.
