Viruses Cheat at Geometry To Infect Cells Faster

Viruses are typically described as tiny, perfectly geometric shells that pack genetic material with mathematical precision, but new research led by scientists at Penn State reveals a deliberate imbalance in their shape that helps them infect their hosts. 

The finding, the researchers say, not only illuminates a fundamental viral strategy but also opens doors for antiviral drug design and molecular delivery technologies critical for vaccines, cancer therapies, medication development and gene editing.

The team published their findings today (Dec. 12) in the journal Science Advances and have filed a patent application related to the discovery. 

“A virus lacks sensory organs, so it uses chemical cues to determine how it replicates its genetic material into new viral packages or assemblies with precise polarity,” said Ganesh Anand, associate professor of chemistry, biochemistry and molecular biology at Penn State and lead author on the study. “This polarity guides the RNA, its genetic material that allows the virus infection to spread, and our research shows that asymmetry is what gives the virus this essential polarity. Viruses build these subtle imperfections into their shells to control how and where their genetic material is packaged and poised to exit during an infection.”

The researchers used advanced imaging techniques, conducted at Penn State’s publicly funded Core Facilities, to study the architecture of the Turnip Crinkle Virus (TCV). This plant pathogen has an icosahedral — or 20-sided — shell that is the same structure as many human pathogens, such as enteroviruses, noroviruses, poliovirus, hepatitis B virus and the virus that causes chickenpox. 

They found that icosahedral viruses use a single chemical bond to tip the scales inside their protein shells to guide release of RNA and infect their hosts. This bond, called an isopeptide link, connects two structural proteins that contribute to the virus’s shell and creates a subtle asymmetry that clusters the virus’s RNA on one side of the particle, ensuring the genetic material exits in one direction when infecting a host.

It can be compared to a trick or “loaded” die, Anand said, referring to dice that are secretly weighted on one side and used to cheat in games. 

“When the virus enters a cell and begins to break apart, this ‘loaded die’ design ensures the genetic material bursts out through a specific exit point — fast and in the right direction — so it can immediately hijack the host’s machinery to make more virus,” Anand said. 

One tiny isopeptide link is responsible for this “loaded die” effect, he explained. It acts like a kind of molecular hinge or strap, anchoring RNA to one half of the particle and putting it slightly off balance to create a spring-loaded genome. When the virus enters its host’s cells and starts to break apart, the RNA is launched out through a specific exit point. 

“The RNA doesn’t just float around,” Anand said. “It’s positioned right where the plant’s ribosomes, its protein-makers, can grab it. This lets the virus start making its own proteins immediately, before the plant can mount a defense.”

The team captured this previously unseen moment, a partially expanded virus poised for release, using two advanced imaging techniques that can monitor microscale changes within cells: cryo-electron microscopy and hydrogen-deuterium exchange mass spectrometry. 

“We were able see the polarity of the particle and it appeared to be positioned somewhere very close to where the RNA looked like it was wanting to get out,” said Varun Venkatakrishnan, a Penn State doctoral student and co-author on the paper who led the cryo-electron microscopy aspects of the work. “This ‘loaded die’ mechanism that we discovered isn’t just a plant virus trick. It could be a universal strategy for how these types of viruses package themselves.”

For human viruses, like those that cause colds or even those that can lead to less common diseases, RNA release is a critical step. Many viruses, like poliovirus or enteroviruses, have icosahedral shells and need to eject their RNA at the right time and place inside a host cell. If they could bias that process, like Turnip Crinkle Virus does, they’d gain speed and precision needed to evade immune defenses, Venkatakrishnan said. 

Finding a way to disrupt the process of RNA release by targeting asymmetric features such as the isopeptide link in Turnip Crinkle Virus could lead to new antiviral therapies or better RNA therapeutics, drugs that prevent infection and autoimmune disorders, explained Sean Braet, a postdoctoral researcher at Penn State and co-author on the paper.

“This could mean designing vaccines that release RNA exactly where it’s needed, near protein-making machinery, to reduce degradation and boost effectiveness of the vaccine,” Braet said. “There is a specific feature on the RNA that can help to direct this process, and now, we’re in the process of figuring out if we can use this naturally occurring phenomena to the advantage of cost-efficiently amplifying expression of therapeutic RNAs in plant virus vectors.”

Antivirals, drugs specifically designed to treat viral infections such as oseltamivir for influenza, could be designed to bind these asymmetrical sites, he added, destabilizing the shape of the shell and preventing the virus from maintaining its spring-loaded state. This would make it harder for the virus to replicate and evolve resistance inside the host. 

"All of this research is very cutting edge and is going on right now,” Anand said. “We have some promising leads.”

Reference: Braet SM, Venkatakrishnan V, Ramesh R, et al. Asymmetric isopeptide bond steers directional genomic RNA egress from icosahedral virus. Sci Adv. 2025;11(50):eady4104. doi: 10.1126/sciadv.ady4104

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