The selection for cidofovir-resistant mutant vaccinia viruses is inhibited by coinfecting cidofovir-sensitive wildtypes

Recent zoonotic mpox outbreaks have underscored the necessity for supplementary therapies to manage these infections and curb virus transmission. Presently, only two antiviral drugs are approved for mpox treatment, and the emergence of drug resistance poses a potential threat to these interventions. In this study, we examined the development of drug resistance within a viral population where the sensitive wildtype strain predominates over the drug-resistant mutant.

Utilizing cidofovir treatment and resistance as a model, we observed that cidofovir-resistant poxviruses outcompete cidofovir-sensitive viruses when they coexist within isolated cells. However, when both strains infect the same cell, the drug-resistant virus loses its competitive edge against the sensitive strain. Our findings indicate that when the two viruses infect separate cells treated with cidofovir, the resistant strain exhibits accelerated genome replication rates compared to the sensitive strain.

Conversely, when the two viruses co-infect the same drug-treated cell, both strains replicate at equivalent rates. This suggests that the drug-resistance trait is functionally shared between the two genetically-distinct strains, enabling the sensitive strain to capitalize on the growth advantage of the resistant strain and counteracting the rapid expansion of the resistant strain.

These results imply that co-infections in poxvirus populations hinder the selection of rare traits like cidofovir-resistance. Given that poxviruses actively thwart superinfection, we propose that superinfection exclusion may sustain fitness within a population and foster the proliferation of rare, beneficial traits in poxvirus communities.