Cryo-EM at Near-Atomic Detail Maps How Andes Hantavirus Grips Human Cells

A study published in Nature has resolved, at near-atomic detail, how the Andes virus spike captures a human receptor — and why most antibodies cannot follow it in. Researchers at Albert Einstein College of Medicine in New York, Institut Pasteur in Paris, and LSU Health Shreveport combined cryo-electron microscopy with functional experiments to map the interaction, work that could redirect antiviral design for a pathogen capable of spreading between people.

Andes virus belongs to the hantaviruses, a group that can turn exposure to infected rodents into life-threatening illness, including a pulmonary syndrome that progresses rapidly to respiratory failure. Andes virus adds a second concern: unlike other hantaviruses known to cause human disease, it can also transmit from person to person. The study, titled "Structural basis for protocadherin-1 recognition by New World hantaviruses," addresses the first step of that infection — attachment.

Why did earlier binding studies fail?

Previous research had established that Andes virus and other New World hantaviruses enter host cells through the cell-surface protein protocadherin-1 (PCDH1). What remained unclear was how the viral spike recognizes this receptor. An isolated spike subunit could not bind PCDH1 at all; the interaction required the assembled, four-part structure.

To examine that assembly, the team engineered a soluble Andes virus spike using methods that included an artificial intelligence–designed scaffold. The scaffold stabilized the square-shaped complex outside the virus, allowing the researchers to combine it with PCDH1 and analyze the resulting structure by cryo-EM.

The images showed that PCDH1 binds asymmetrically within a deep central pocket formed by four copies of the viral Gn glycoprotein. Rather than presenting a receptor-binding site on any individual subunit, the spike constructs one through the arrangement of its components — a finding that explains why earlier work with isolated subunits came up empty.

What did mutagenesis and antibodies reveal?

Mutagenesis experiments identified three Gn loops that shape the binding site. Changes involving these loops also allowed the researchers to transfer PCDH1-binding ability from New World to Old World hantavirus glycoproteins, according to the paper.

The team then tested four neutralizing antibodies. Structural and functional analyses showed the antibodies prevent receptor binding through two mechanisms: obstructing access to the PCDH1-binding site, or creating a physical barrier that stops receptor engagement.

"The depth of this pocket also helps explain how the virus limits antibody access. What's striking is how the same pocket can accommodate the receptor while restricting antibody access. PCDH1's long, slender shape lets it reach deep inside, but most antibodies are too bulky to follow," said Rohit Jangra, PhD, assistant professor of microbiology and immunology at LSU Health Shreveport.

That geometry points toward a design constraint for therapeutics. Engineered molecules with a narrow, elongated shape might reach farther into the pocket and block attachment, the researchers argue — a target profile that conventional bulky antibodies do not satisfy.

What comes next?

The authors summarize the work plainly in their paper: "Together, these findings define the structural determinants of hantavirus–receptor recognition, reveal how a virus can mask its receptor-binding site by recessing it in a surface depression and how antibodies can counter this strategy, and provide a framework for the design of antiviral therapeutics targeting the hantavirus spike."

The team intends to explore the pocket as a basis for antiviral strategies against Andes virus and potentially related pathogens, including Sin Nombre virus.