Homologous recombination is an intrinsic defense against antiviral RNA interference

Abstract

<p id="d7752019e221">In an effort to determine whether host defenses can significantly influence the prevalence of different virus groups, we applied identical selective pressures onto four families of diverse viruses. Using an RNAi-like defense, we found that the capacity of positive-stranded RNA viruses to switch genomic templates during replication conferred an adaptability that exceeded that of negative-stranded RNA viruses that were less able to perform this biology. Together, this work suggests that in the absence of an antiviral antagonist, fundamental aspects of virus biology can provide an inherent advantage to evade host defenses. </p><p class="first" id="d7752019e224">RNA interference (RNAi) is the major antiviral defense mechanism of plants and invertebrates, rendering the capacity to evade it a defining factor in shaping the viral landscape. Here we sought to determine whether different virus replication strategies provided any inherent capacity to evade RNAi in the absence of an antagonist. Through the exploitation of host microRNAs, we recreated an RNAi-like environment in vertebrates and directly compared the capacity of positive- and negative-stranded RNA viruses to cope with this selective pressure. Applying this defense against four distinct viral families revealed that the capacity to undergo homologous recombination was the defining attribute that enabled evasion of this defense. Independent of gene expression strategy, positive-stranded RNA viruses that could undergo strand switching rapidly excised genomic material, while negative-stranded viruses were effectively targeted and cleared upon RNAi-based selection. These data suggest a dynamic relationship between host antiviral defenses and the biology of virus replication in shaping pathogen prevalence. </p>