Evidence of two Lyssavirus phylogroups with distinct pathogenicity and immunogenicity

The genetic diversity of representative members of the Lyssavirus genus (ra bies and rabies-related viruses) was evaluated using the gene encoding the transmembrane glycoprotein involved in the virus-host interaction, immunoge nicity, and pathogenicity. Phylogenetic analysis distinguished seven genoty pes, which could be divided into two major phylogroups having the highest b ootstrap values. Phylogroup I comprises the worldwide genotype 1 (classic R abies virus), the European bat lyssavirus (EBL) genotypes 5 (EBL1) and 6 (E BL2), the African genotype 4 (Duvenhage virus), and the Australian bat lyss avirus genotype 7, Phylogroup II comprises the divergent African genotypes 2 (Lagos bat virus) and 3 (Mokola virus), We studied immunogenic and pathog enic properties to investigate the biological significance of this phylogen etic grouping. Viruses from phylogroup I (Rabies virus and EBL1) were found to be pathogenic for mice when injected by the intracerebral or the intram uscular route, whereas viruses from phylogroup II (Mokola and Lagos bat vir uses) were only pathogenic by the intracerebral route. We showed that the g lycoprotein R333 residue essential for virulence was naturally replaced by a D333 in the phylogroup II viruses, likely resulting in their attenuated p athogenicity. Moreover, cross-neutralization distinguished the same phylogr oups. Within each phylogroup, the amino acid sequence of the glycoprotein e ctodomain was at least 74% identical, and antiglycoprotein virus-neutralizi ng antibodies displayed cross-neutralization. Between phylogroups, the iden tity was less than 64.5% and the cross-neutralization was absent, explainin g why the classical rabies vaccines (phylogroup I) cannot protect against l yssaviruses from phylogroup II. Our tree-axial analysis divided lyssaviruse s into two phylogroups that more closely reflect their biological character istics than previous serotypes and genotypes.