A Step Towards Needed Treatments for Hantaviruses in New Molecular Map
An innovative imaging technique enabled dramatically higher resolution structures than previous efforts.
This is the highest resolution molecular structure ever constructed of a key protein complex on the surface of the Andes virus, called the Gn-Gc tetramer, that enables it to infect cells. Credit: University of Texas at Austin.
Hantaviruses, transmitted from rodents to people, have a death rate approaching 40%. They’re found around the world, and because there are no approved vaccines or treatments, they’re among the pathogens of highest concern for future pandemics. They made news in the United States last year when Betsy Arakawa, the wife of actor Gene Hackman, died from a hantavirus infection in New Mexico in March.
New findings published in the journal Cell about the Andes virus, a hantavirus endemic to the southwestern U.S. and other parts of North and South America, represent a crucial first step towards much-needed vaccines and antibody therapies for this and other hantaviruses.
A team led by researchers at The University of Texas at Austin has produced a detailed blueprint, the highest resolution yet, for a protein complex the Andes virus uses to infect host cells. Having this structure, essentially a 3D map showing the complex shapes of molecules at the nanoscale, is a precursor for vaccine development and the creation of antibody therapies. The new detailed structural information enabled the researchers to produce a vaccine candidate that, when injected in mice, caused their cells to produce neutralizing antibodies against the Andes virus.
“Now that we have a better blueprint of what the virus looks like, we can design effective vaccines and antibody therapies for hantaviruses,” said Jason McLellan, professor of molecular biosciences and the Robert A. Welch Chair in Chemistry at UT Austin, who led the research. Luqiang Guo, a postdoctoral fellow at UT Austin, is the first author.
This work was funded in part by the National Institutes of Health (NIH), the Welch Foundation and the Cancer Prevention and Research Institute of Texas.
This surface protein complex for the Andes virus is a mushroom-shaped structure called a Gn-Gc tetramer. To map the 3D structures, the team first produced virus-like particles that mimic a real virus, but without the genome that makes a virus infectious. They then used a cryo-electron microscope—which shines an electron beam through a frozen sample and detects the shadows created by molecules—to reconstruct the three-dimensional structures of the Gn-Gc tetramers on the surface of the virus-like particles.
But there was a twist: To obtain extremely high-resolution structures, the researchers painstakingly identified and isolated shadows from only the tetramers that were pointing sidewise relative to the electron beam and ignored those pointing in other directions. This allowed them to borrow a reconstruction method typically used on individual proteins. The resulting structures have an extremely high resolution of 2.3 angstroms, meaning details the size of just a couple of atoms were effectively captured. That’s enough to represent a transformational improvement over another team’s model of the tetramer from a few years ago, at a resolution of 12 angstroms, still tiny but large enough to produce some key inaccuracies – ones effectively corrected with the newer method and resulting structure.
“People will start to apply this method to many other viruses,” McLellan predicted.
These latest structures show the Gn-Gc tetramer in a particular state before it has infected a cell. For vaccines or antibody therapies to be most effective against a hantavirus, mimicking surface proteins at this pre-infection stage is essential. Such surface proteins change once they have fused with the cell through the infection process, so a future goal of the team is to find small tweaks to the recipe for these viral protein complexes that help lock them in place, using what are called stabilizing mutations. The scientists plan to use artificial intelligence tools to assist in the process of identifying suitable mutations.
In 2024, the NIH identified several families of viruses—including hantaviruses—that were extremely dangerous and had no effective vaccines or treatments, making them of special concern for their potential to cause a pandemic. To better prepare for future pandemics, the NIH awarded a series of grants through the ReVAMPP program to study these viruses and develop new tools to combat them, including the grant that established the Provident consortium and enabled this latest study. McLellan and other Provident researchers have simultaneously been working to find ways to address other viruses that health officials have identified as especially dangerous in an outbreak, such as measles and Nipah virus.
Kartik Chandran, a professor of microbiology and immunology at Albert Einstein College of Medicine and principal investigator for Provident, is the co-senior author of this latest study. Collaborators at Texas A&M University and The University of Texas Southwestern Medical Center provided cryo-EM facilities for obtaining structures, and researchers with HDT Bio in Seattle contributed to the publication. Other UT Austin researchers involved in the work were Zunlong Ke, an assistant professor of molecular biosciences, and cell and molecular biology graduate student Elizabeth McFadden.
