Human noroviruses are responsible for the majority of cases of epidemic non-bacterial gastroenteritis. Despite their importance as human pathogens, knowledge of the viral life cycle and host pathogenesis is limited due to the lack of practical models to study. In contrast, murine norovirus: MNV) has been a critical surrogate for the study of human noroviruses as it is the only member of this genus that establishes infection in a small animal model, can be grown in cell culture, and has a reverse genetics system. Noroviruses are divided into genogroups which can contain many viral strains. These viral strains can display dramatic variation in their virulence and ability to persist, but the factors responsible for these differences are poorly defined. The focus of this work is to describe biological differences between two MNV strains, CW3 and CR6, and to use molecular genetics tools to identify the viral determinants that contribute to these differences. Here, we have cloned CW3 and CR6 into a reverse genetics system for production of virus and genetic analysis. We show virus production by this method limits the emergence of viral quasispecies. This makes the analysis of biological phenotypes less complex. We identify four phenotypes in which our cloned viruses behave differently from one another and have chosen two, lethality in STAT1-/- mice and persistent infection in wild type mice, for further study. We show that the sequence of the protruding: P) domain of the viral capsid protein determines whether MNV infection is lethal in mice lacking STAT1, a regulator of innate immunity. The P domain is also a determinant of viral growth and dissemination in these mice. Further, we have identified the N-terminal non-structural protein: NTerm) as the viral determinant of persistent infection in wild type mice. Remarkably, a single amino acid in NTerm dictates the persistence phenotype of these two viral strains. This is the first demonstration of a function for the norovirus NTerm protein during infection of a host. We ...