Structure uncovered for Lassa virus glycoprotein

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A 10-year project studying Lassa virus has uncovered both structural and functional details of a crucial viral protein. The team hope this new information could aid vaccine development and new therapeutics.

Lassa virus, a member of the arenavirus family, is endemic to Africa and is spread via rodents and their feces. It’s estimated that there are up to 300,000 Lassa infections each year, with fatality rates at approximately 1–10%.

Lassa virus only possesses one antigen on its viral surface – the Lassa glycoprotein precursor complex (GPC) – which is known to mediate viral binding and entry to host cells. Understanding the structure this protein is therefore crucial to vaccine development.

Currently, due to the diversity and instability of the GPC protein, the structure remains unsolved for all of the viruses in the arenavirus family. This study, which presents the crystal structure of Lassa GCP bound to a human neutralizing antibody, is therefore a huge breakthrough.

The researchers re-engineered the GCP protein in order to stabilize it, and resolved the structure at 3.2-angstrom resolution. They also investigated the structure by studying the interaction of GCP with antibodies taken from Lassa survivors.

The team also uncovered more about how the molecule is assembled with biochemical analyses suggesting that antibodies neutralize GCP by inhibiting the conformational changes required for entry.

Lassa was recently identified by The Coalition for Epidemic Preparedness as a priority for vaccine development, and the team hope their findings will provide a template for this. Senior author Ollmann Saphire (The Scripps Research Institute, CA, USA) concluded: “This was a tenacious effort – over a decade – to conquer a global threat,”

“The Scripps Research Institute has an institutional expertise in understanding viral structures and antibodies – and in designing vaccines. This study goes even further. The research started from scratch with the native, wild-type viruses in patients in a remote clinic—and went all the way to developing a basis for vaccine design.”

Sources: Hastie KM, Zandonatti MA, Kleinfelter LM et al. Structural basis for antibody-mediated neutralization of Lassa virus. Science. 356(6341), 923–928 (2017); https://www.scripps.edu/news/press/2017/20170531ollmannsaphire.html

Interested? You can find out more about Lassa virus as a pandemic threat in our editorial.

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