Nature: Hantavirus Enters Human Cells Through a Groove in a Receptor-Binding Protein

Hantaviruses are a large family of viruses transmitted primarily by rodents. They can cause severe, sometimes fatal illnesses, including hantavirus pulmonary syndrome. Of the more than 20 hantaviruses known to infect humans, the Andes virus is the only one known to spread from person to person.

The discovery could pave the way for effective treatments against the Andes virus and other hantaviruses.

“Eight years ago, we discovered that the Andes virus infects human cells using a specific protein on the cell surface called a receptor, but we could not understand exactly how the virus recognizes it. Our latest work solves this mystery: we reveal a new way the virus can capture its receptor during infection and suggest how we might fight back with therapies designed to exploit this emerging viral vulnerability,” says study co-author Kartik Chandran.

The team previously showed that, to infect a cell, the spike protein on the surface of the Andes virus must attach to the PCDH1 receptor. However, exactly how this interaction occurs remained unclear.

In most viruses, including SARS-CoV-2, the spike protein consists of three identical units, each with its own receptor-binding site. The Andes virus spike protein, by contrast, consists of four units arranged in a square. Unlike the SARS-CoV-2 spike protein, a single unit cannot bind to the receptor: the entire four-unit structure is required to capture PCDH1.

To examine the structure in detail, the researchers used cryo-electron microscopy. They also had to develop new techniques, including an artificially designed AI-generated scaffold, to keep the square-shaped Andes virus spike protein intact in a test tube.

The researchers found that a single PCDH1 molecule fits into the very center of the spike protein, binding to a deep groove, or “pocket,” in its middle.

The pocket’s depth also helps explain how the virus limits antibody access. “PCDH1 has a long, slender shape that allows it to penetrate deep inside, but most antibodies are too bulky to follow it,” says Rohit Jangra of LSU Health Shreveport.

The researchers also examined antibodies isolated from patients infected with hantavirus. Some can bind close enough to the entrance of the pocket to prevent PCDH1 from entering, but they cannot penetrate as deeply as the receptor itself.

This points to a sophisticated way for the virus to evade antibodies, while also revealing a potential vulnerability. Although the structure of human antibodies limits how deeply they can reach, scientists could design “long and slender” molecules capable of blocking the pocket.