Undergraduate Researcher Explores How Viruses and Their Parasites Evolve Together

Shriv Muthupandiyan

Viruses have parasites of their own, and those tiny hitchhikers may help determine how viruses change, survive and respond to treatment. Undergraduate researcher Shiv Muthupandiyan of the John Yin Lab at the Wisconsin Institute for Discovery is the lead author of a new study examining how defective interfering particles, or DIPs, evolve alongside viruses and shape their behavior.

DIPs are mutant viral particles that act like parasites of viruses, using their resources to reproduce while slowing the virus’s growth. DIPs can arise during a typical viral infection. Because DIPs cannot replicate on their own, they rely on the virus’s replication machinery to reproduce. In doing so, they consume resources within an infected cell, thereby interfering with viral replication. This could make them useful in developing new antiviral therapies.

Researchers have already been engineering DIP-like particles into antivirals which are called therapeutic interfering particles (TIPs). They have shown promise in preclinical studies against influenza, polio, SARS-CoV-2, and HIV-1. Unlike conventional drugs, which are given in fixed doses and do not reproduce, these particles replicate and adapt alongside the virus. The model explores whether the virus can evolve to escape their effects.

“Viruses and DIPs play a kind of cat-and-mouse game: the viruses evolve in ways that make it harder for the DIPs to reproduce, and the DIPs evolve right back to keep up,” says Muthupandiyan. “Our paper is a new way of thinking about how that chase plays out.”  The findings suggest that DIPs may play a larger role in viral evolution than previously understood. To understand why viruses change the way they do, researchers may need to consider the parasitic particles riding along with them and whether they could be engineered into new antiviral therapies.

“Much of the earlier modeling assumed that mutations are rare and that a virus population behaves like a single entity changing slowly, one step at a time,” says Muthupandiyan. “They also tended to treat the interfering particle as a fixed target that the virus evolves against. But viruses mutate constantly and exist as diverse swarms, and their DIPs are mutating right alongside them. Our work tackles that strong-mutation regime, where the virus and the DIPs are both continuously evolving and adapting to each other at the same time.”

To study this interaction, the researchers developed a mathematical model that looks at continuous traits, such as how quickly viruses and DIPs grow or how strongly DIPs interfere with viral replication. The model allowed those traits to change over time, giving researchers a way to explore how viruses and DIPs might evolve together.

The results showed that at the population level, viruses and DIPs can rise and fall in repeating cycles that resemble predator–prey interactions, even when traits stay fixed. However, with evolution, the viruses may shift traits to escape interference, while new DIPs can emerge and adapt in response. This coevolutionary chase is a feature that sets DIPs apart from conventional therapies, which cannot adjust to viral change. By exploring a wide range of conditions, the researchers identified when viruses and DIPs coexist, when one eliminates the other, and when they remain locked in long-term pursuit. 

Which outcome happens depends on conditions such as how strongly the DIPs interfere with viral replication and how costly it is for the virus to evolve resistance. When escape comes with a steep cost, the virus can become trapped and stay suppressed. That is exactly the kind of situation researchers may want to engineer if DIPs are going to be used as antiviral therapies.

This research offers a framework for thinking about virus–DIP coevolution and offers predictions that can be tested in the lab. For virologists, it points to DIPs as an under appreciated force in viral evolution. For scientists who use mathematics to study living systems, it presents a rich coevolution problem and foundation to build new models for understanding how viruses and DIPs change together. The project also highlights the value of undergraduate research, giving students opportunities to contribute to fundamental questions in biology while advancing knowledge that could help shape future antiviral therapies.

Muthupandiyan hopes the work will encourage more researchers to investigate how DIPs shape viral evolution and how that knowledge could guide the design of future antiviral therapies.

-Laura RedEagle

This work was supported by funding from the US National Science Foundation (NSF) under grants DMS-2151959 (J.Y.), MCB-2029281 (J.Y.), and CBET-2030750 (J.Y.); and the National Institutes of Health (NIH) under awards OT2OD030524 (J.Y.) and R01DK133605 (J.Y.).