Dynamics of rabies virus quasispecies during serial passages in heterologous hosts

To understand the mutations and genetic rearrangements that allow rabies vi rus infections of new hosts and adaptation in nature, the quasispecies stru cture of the nucleoprotein and glycoprotein genes as well as two noncoding sequences of a rabies virus genome were determined, Gene sequences were obt ained from the brain and from the salivary glands of the original host, a n aturally infected European fox, and after serial passages in mice, dogs, ca ts and cell culture. A relative genetic stasis of the consensus sequences c onfirmed previous results about the stability of rabies virus. At the quasi species level, the mutation frequency varies, in the following order: glyco protein region (21.9 x 10(-4) mutations per bp), noncoding sequence nucleop rotein-phosphoprotein region (7.2-7.9 x 10(-4) mutations per bp) and nucleo protein gene region (2.9-3.7 x 10(-4) mutations per bp), These frequencies varied according to the number, type of heterologous passages and the genom ic region considered. The shape of the quasispecies structure was dramatica lly modified by passages in mice, in which the mutation frequencies increas ed by 12-31 x 10(-4) mutations per bp, depending on the region considered. Nonsynonymous mutations were preponderant particularly in the glycoprotein gene, stressing the importance of positive selection in the maintenance and fixation of substitutions. Two mechanisms of genomic evolution of the rabi es virus quasispecies, while adapting to environmental changes, have been i dentified: a limited accumulation of mutations with no replacement of the o riginal master sequence and a less frequent but rapid selective overgrowth of favoured variants.