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Summary In contrast to RNA viruses, double-stranded DNA viruses have low mutation rates, yet must still adapt rapidly in response to changing host defenses. To determine mechanisms of adaptation we subjected the model poxvirus vaccinia to serial propagation in human cells, where its anti-host factor K3L is maladapted against the anti-viral Protein Kinase R (PKR). Viruses rapidly acquired higher fitness via recurrent K3L gene amplifications, incurring up to 7-10% increases in genome size. These transient gene expansions were necessary and sufficient to counteract human PKR and facilitated the gain of an adaptive amino acid substitution in K3L that also defeats PKR. Subsequent reductions in gene amplifications offset the costs associated with larger genome size while retaining adaptive substitutions. Our discovery of viral ‘gene-accordions’ explains how poxviruses can rapidly adapt to defeat different host defenses despite low mutation rates and reveals how classical Red Queen conflicts can progress through unrecognized intermediates.

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