Big picture: the feedback loop between viral density leading to social interaction, which leads to realized phenotype, which alters fitness, leading to new viral densities, should be considered when designing optimal treatments.

When we simulated clinical trials using weaker drugs, they cleared later on average (mostly due to fewer early clearers). But the overall viral load was lower in the x100 group, and resistance frequency was likewise reduced.

Counterintuitively, our model suggests that a weaker treatment may maintain enough coinfection to keep resistant viruses wrapped in susceptible capsids, while still maintaining low viral load.

The reason for this was due to the effectiveness of the treatment. As the treatment works, viral density collapses, coinfection plummets, and genotypes become linked to their phenotype. Resistant genomes are wrapped in their own proteins, and the drug now selects for them.

Adding a simple immune clearance step to our model and running out over multiple generations lets the model reproduce the pattern observed in the clinical trial, where late clearers predominantly had resistant infections.

At high density, viruses have a much higher rate of coinfection. Rare resistant genomes get packaged into capsids with lots of susceptible proteins. This means that the drug works well and resistance is suppressed.

Our model captures the dynamics observed in cell culture, where coinfection with larger susceptible virus populations reduces resistant viral yield. We realized, however, that the MOI was quite large, and this was only a single round of passaging.

So what gives? To investigate this discrepancy, we built an eco-evolutionary model for poliovirus treated by pocapavir and found that 𝐚 𝐬𝐢𝐧𝐠𝐥𝐞 𝐦𝐨𝐝𝐞𝐥 𝐜𝐨𝐮𝐥𝐝 𝐞𝐱𝐩𝐥𝐚𝐢𝐧 𝐛𝐨𝐭𝐡 𝐨𝐮𝐭𝐜𝐨𝐦𝐞𝐬.

However, clinical trials with pocapavir had mixed results. In 3/4 placebo-matched groups, pocapavir did not significantly reduce clearance time in people infected with OPV. Additionally, resistance evolved in nearly half of the experimental group, highly enriched compared to placebo.

A previous study by Tanner et al. showed the power of this phenomenon. They studied pocapavir, a capsid inhibitor that targets poliovirus. In coinfected cells, increasing amounts of susceptible viruses decreased resistant virus output, suggesting that resistance should be hard to evolve in PV.

First, some background. Most organisms have a direct link between their genotype and their phenotype. However, since viruses replicate inside of cells, different genotypes can co-occupy a cell and “share” their proteins with each other.