Most organisms make a significant effort to maintain the integrity of their genome during replication, encoding complex systems to ensure few mutations are made and passed on to the next generation. However, RNA viruses have the highest error frequencies observed in nature, and thrive under these conditions. Error-prone viruses such as hepatitis C virus and HIV are among the most successful pathogens on the planet and continue to challenge the development of therapies. Because of their high error and replication rates, it is thought that, for some RNA viruses, every possible mutation is made every day within an infected host. However, only a small subset of viruses in this mixed population, or quasispecies, survives and continues to replicate. We are interested in the contraction and expansion of the viral quasispecies, both within an infected host and in transmission between hosts. Using poliovirus as a model, we found that host barriers can limit viral quasispecies spread within an infected animal, possibly limiting the pathogenesis of viral infection by limiting the diversity of the population. We are analyzing the mechanisms and consequences of these host barriers on viral pathogenesis. Our overall goal is to understand viral and host determinants of viral genome evolution to aid vaccine design and to prevent treatment failure.