Using low-temperature electron microscopy, scientists at Scripps Research and the University of Amsterdam report they have mapped critical proteins that cover the surface of the hepatitis C virus (HCV) and enable it to enter host cells.

The findings were published in Science in an article titled, “Structure of the hepatitis C virus E1E2 glycoprotein complex.”

“HCV infection is a leading cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma in humans and afflicts more than 58 million people worldwide,” wrote the researchers. “The HCV envelope E1 and E2 glycoproteins are essential for viral entry and comprise the primary antigenic target for neutralizing antibody responses. The molecular mechanisms of E1E2 assembly, as well as how the E1E2 heterodimer binds broadly neutralizing antibodies, remain elusive. Here, we present the cryo–electron microscopy structure of the membrane-extracted full-length E1E2 heterodimer in complex with three broadly neutralizing antibodies—AR4A, AT1209, and IGH505—at ~3.5-angstrom resolution.”

“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.

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 in studying HCV’s envelope protein complex, which 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,” said co-first author Lisa Eshun-Wilson, PhD, a postdoctoral research associate in both the Lander and Ward labs at Scripps Research.

The researchers discovered that they could use a combination of three broadly neutralizing anti-HCV antibodies to stabilize the E1E2 complex in a natural conformation. 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.

These findings may aid researchers in potentially designing a vaccine that powerfully elicits these antibodies to block HCV infection.

“The structural data also should allow us to discover the mechanisms by which these antibodies neutralize HCV,” said co-first author Alba Torrents de la Peña, PhD, a postdoctoral researcher in the Ward lab.