The important roles of the spike protein and other structural proteins in murine coronavirus (MHV) pathogenesis have been demonstrated; however, the role of the replicase gene remains unexplored. We assessed the influence of the replicase genes of the highly neurovirulent MHV-JHM strain and the hepatotropic and mildly neurovirulent A59 strain in acute infection of the mouse. Analysis of chimeric A59/JHM recombinant viruses indicates that the replicase genes are interchangeable and that it is the 3โ€ฒ end of the genome, encoding the structural proteins, rather than the replicase gene, that determines the pathogenic properties of these chimeras. Copyright ยฉ 2007, American Society for Microbiology.