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The researchers determined the structure of key hepatitis C virus proteins bound to three neutralizing antibodies. The findings provide new insights into how the virus invades cells and could inform the development of vaccines or antiviral therapies.
Hepatitis C is one of the leading causes of long-term liver disease and liver cancer. Caused by a virus, it affects an estimated 58 million people worldwide. Hepatitis C is one of the most common bloodborne infections in the United States.
Despite years of effort, researchers have yet to develop an effective vaccine that will prevent infection. One hurdle has been that scientists only partially understand how the virus infects liver cells and evades antibodies.
Researchers have long known that the outer surface of the virus includes two envelope proteins called E1 and E2. These proteins come together to form a complex called E1E2. This protein complex covers the outer surface of the virus and helps it enter liver cells, although the mechanism is unclear. As the only protein on the viral surface, the E1E2 assembly is also the primary target for neutralizing antibodies.
Previous studies have uncovered high-resolution structures for portions of E1 or E2 proteins. But detailed features of the E1E2 complex have been elusive, in part because the two isolated proteins form a loose, fragile pairing that is difficult to see at high resolution.
An international research team led by Dr. Andrew B. Ward of the Scripps Research Institute found a way to overcome this difficulty. The scientists found that they could stabilize the entire E1E2 complex by including a neutralizing antibody. The antibody helps stabilize the E1E2 complex in a more natural configuration. For further analysis, the researchers added two more neutralizing antibodies.
They then used cryo-electron microscopy and advanced imaging software to look at the structural details of E1E2 bound to the antibodies. This approach allowed scientists to view the E1E2 complex, along with neutralizing antibodies, at near-atomic resolution. Their findings appeared in Science on October 21, 2022.
The structural analyzes were generally consistent with previous studies that examined portions of the viral proteins via X-ray crystallography. The team was able to model 51% of E1 and 82% of E2, including the crucial parts where they interact. The structure also revealed previously unrecognized aspects of the links between neutralizing antibodies and viral proteins.
Additionally, the analysis exposed new details about the role of sugar-related molecules called glycans. Glycans help hide viruses from the immune system and are a prominent component of the E1E2 complex. The glycans, the researchers found, don’t just help mask viral regions that could be attacked by antibodies. They also play a stabilizing role by helping to hold the fragile E1E2 complex together.
The analysis sheds light on structural changes that could allow the virus to fuse with and gain access to liver cells. Such details could help guide the development of structure-based vaccines and antiviral therapies.
“This long-sought structural information about the hepatitis C virus puts a wealth of previous observations into structural context and paves the way for rational vaccine design against this incredibly difficult target,” says Ward.
—by Vicki Contie
References: Structure of the E1E2 glycoprotein complex of hepatitis C virus. Torrents de la Peña A, Sliepen K, Eshun-Wilson L, Newby ML, Allen JD, Zon I, Koekkoek S, Chumbe A, Crispin M, Schinkel J, Lander GC, Sanders RW, Ward AB. Sciences. 2022 October 21; 378 (6617): 263-269. doi: 10.1126/science.abn9884. Epub Oct 20, 2022. PMID: 36264808.
Money: NIH National Institute of General Medical Sciences (NIGMS), National Science Foundation, Netherlands Organization for Scientific Research, Amsterdam Institute for Infection and Immunity, Bill and Melinda Gates Foundation.
Source: news.google.com