Social lives of viruses affect antiviral effectiveness

Interactions among viruses can help them succeed inside their hosts or impart vulnerabilities that make them easier to treat. Scientists are learning the ways viruses mingle inside the cells they infect, as well as the consequences of their socializing. 

Ph.D. student Alexander J. Robertson in the Molecular & Cellular Biology program at the University of Washington is among those scientists. 

“I study the evolution of antimicrobial resistance through mechanisms which require interaction between microbes,” he explained.

This week he is the lead author of a paper in Nature Ecology & Evolution on that topic.

Polioviruses can cause gut infections that, in some cases, enter the nervous system and cause paralysis. Although vaccines made the disease almost extinct around the world, cases are once again beginning to rise in Pakistan and Afghanistan, according to the World Health Organization. This hastens the need to test new therapies. 

“We developed a mathematical model to explain why the most promising poliovirus antiviral, pocapavir, has shown limited success in clinical trials despite encouraging indications from cell culture,” Roberston said. 

He is a graduate student researcher mentored by senior authors Alison Feder and Ben Kerr. Feder’s Department of Genome Sciences lab at the UW School of Medicine studies the rapid evolution of pathogens and cancers. Kerr’s lab in the UW Department of Biology in the UW College of Arts & Sciences combines math, computer simulation and experiments addressing ecology and evolutionary biology.

“The key insight in our paper is counterintuitive,” explained Feder, an assistant professor of genome sciences and a Freeman Hrabowski Scholar at the Howard Hughes Medical Institute. “Pocapavir’s success depends on viruses interacting inside the same cell. But when treatment reduces the viral population as intended, those interactions can unintentionally vanish.” 

Although it’s debated whether viruses are living things, these gray-zone biological entities still can compete, cooperate or share genomic resources with each other in a microbial potluck. These collective efforts among viruses appear to influence their susceptibility or resistance to efforts to vanquish them. Socializing among viruses can favor the emergence of new variants but may alternatively impede new strains. 

Examining viruses’ communal responses in the presence of specific challenges, such as antiviral drugs, might also help medical researchers produce more effective treatments. 

Pocapavir, the investigational antiviral drug studied, can allow susceptible polioviruses to sensitize resistant ones. Although this strategy seemed to work in previous lab culture studies of the virus, in a clinical trial, polioviruses evolved widespread resistance to the drug.

The latest UW study found that initially using pocapavir amid a high density of poliovirus enabled it to work as planned: susceptible viruses sensitized resistant ones. However, over successive generations of viruses, the highly potent drug shrunk the population density of the poliovirus such that fewer viruses infected the same cells at the same time. 

With a smaller population, resistant viruses no longer had to share their cells with susceptible ones, and resistance was able to evolve. 

Although it seemed contradictory, the researchers demonstrated that lowering the potency of pocapavir could improve the situation by enhancing the survival of enough susceptible viruses to continue sensitizing the resistant ones. 

The findings, while not a clinical recommendation, might lead to examining antiviral dosing strategies that enhance the opportunity for coinfection between susceptible and resistant viruses, thereby limiting subsequent resistance to the drug and avoiding rebounds. 

The findings, the authors noted, suggest a trade-off for antivirals that rely on viruses interacting: Hitting the virus hard can clear the infection quickly but may allow resistance to rise. A gentler approach may take longer but might help keep resistant strains from taking over and spreading to other people.  By promoting social interactions in viruses in this way, a less potent drug may ironically improve its future utility.

This work was funded by the National Institutes of Health (T32-GM136534-02) and the Environmental Biology Division at the National Science Foundation (2142718).

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