Andes Hantavirus Uses a Four-Part Spike Pocket to Bind Human Cells

The Andes virus hides its human-cell receptor-binding site in a pocket that antibodies may struggle to enter. A new structural study shows how the virus’s assembled spike binds protocadherin-1 (PCDH1), a protein on human cells, and how neutralizing antibodies can block that interaction. The work focuses on a basic problem in viral entry: a virus must attach to a cell, but the shape that enables attachment can also affect how well the immune system reaches it.

Researchers from Albert Einstein College of Medicine, Institut Pasteur and LSU Health Shreveport combined cryo-electron microscopy (cryo-EM) with functional experiments to map the interaction in near-atomic detail. The findings, published in Nature, could help guide efforts to interrupt infection by Andes virus and related hantaviruses. The study doesn’t show that a treatment is ready, but it offers a clearer picture of where the virus meets its receptor and what might interfere with that contact.

A binding site built by the full spike

Earlier research had established that Andes virus and other New World hantaviruses use PCDH1, a protein on the surface of human cells, to gain entry. But knowing which receptor a virus uses doesn’t by itself explain how the two molecules fit together. An isolated spike subunit couldn’t bind PCDH1, suggesting that the relevant shape isn’t present on a single piece of the viral machinery.

Instead, the receptor interacts with the complete, four-part spike assembly. That distinction matters because studies of isolated viral proteins can miss binding surfaces that only appear when the parts assemble. Here, receptor recognition depends on the geometry created by the whole structure.

To capture the assembly for imaging, the team engineered a soluble Andes virus spike and used an artificial intelligence–designed scaffold to stabilize its square-shaped structure outside the virus. They then combined it with PCDH1 and analyzed the complex using cryo-EM. The scaffold served as a way to hold the spike in a form researchers could examine; the resulting structure gives a view of the interaction that would be difficult to infer from the subunits alone.

The resulting images showed PCDH1 sitting asymmetrically inside a deep central pocket formed by four copies of the viral Gn glycoprotein. The receptor-binding site, in other words, emerges from how the spike’s parts fit together rather than from a single subunit. This is more significant than it looks: the same assembly that creates the docking site also determines how exposed that site is to other molecules.

Mutagenesis experiments pointed to three Gn loops that help shape the pocket. By changing these parts of the glycoprotein, the researchers could test which features contribute to receptor recognition, rather than relying on the image alone. Alterations to those loops also allowed the researchers to transfer PCDH1-binding ability from New World hantavirus glycoproteins to Old World ones, according to the paper. That result connects the pocket’s structure to a measurable function across these virus groups.

Why antibodies have trouble reaching the pocket

The team tested four neutralizing antibodies and found two ways they stop receptor binding: some obstruct access to the PCDH1 site, while others form a physical barrier that prevents the receptor from engaging. The distinction suggests that antibodies can interfere with the same entry process through different positions around the spike. It also shows why simply identifying an antibody that neutralizes a virus may not reveal how it works; the structural details help explain the block.

The pocket’s depth may help explain this difference. PCDH1’s long, slender form can reach inside, while the bulkier antibodies have limited access. “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 raises a practical question for antiviral research: could a molecule be designed to reach into the pocket where many antibodies can’t? The structural contrast suggests a possible design principle for antiviral candidates, with engineered molecules shaped to be narrow and elongated enough to penetrate the site and block attachment. That remains a research direction, not evidence that such a candidate will work in an organism or become a medicine.

The researchers plan to investigate the vulnerability for Andes virus and potentially related pathogens, including Sin Nombre virus. If you're working in this space, the transferable binding result may be as useful as the antibody findings: it points to features of the spike that can change receptor recognition across hantavirus groups. And yet, the study’s implications will depend on whether those structural observations translate into ways to prevent infection.

What the structure clarifies—and what comes next

The work provides a framework for thinking about both viral attachment and immune access. A recessed binding site can let a receptor reach the spike while limiting the approach of larger antibodies; the same physical feature can therefore support infection and complicate neutralization. (And this is the part most people overlook.) A pocket isn’t just a place where binding happens. Its shape can influence which molecules get close enough to compete.

The authors wrote, “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 study, “Structural basis for protocadherin-1 recognition by New World hantaviruses,” outlines how the spike’s architecture enables receptor capture while limiting antibody access. For now, the clearest outcome is a more detailed structural account of that tradeoff. A starting point, not a finished intervention.

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