To study the molecular basis of virulence of viral haemorrhagic septicaemia virus (VHSV), we used a cross-reactive neutralizing MAb to select MAb-resistant (MAR) mutants with reduced pathogenicity for fish. From sequence determination of the G gene of MAR mutants, attenuated laboratory variant and avirulent field strains, we identified two distant regions of the glycoprotein associated with virulence: region I (aa 135-161), homologous to the putative fusion peptide of both rabies virus (RV) and vesicular stomatitis virus (VSV), and region II (surrounding aa 431-433), homologous to RV and VSV domains controlling the conformational changes necessary for the fusion process to take place. Simultaneous mutations in both regions resulted in the most attenuated phenotype and we obtained genetic evidence that regions I and II may be structurally linked. As the MAR mutants had mutations in or near domains involved in fusion, the fusion properties of VHSV and its variants were analysed. This work allowed us to postulate that the fusion domain of VHSV is probably constituted of two distinct regions of the protein connected through a disulfide bridge between cysteines 110 and 152. Finally, we obtained evidence suggesting that the pH threshold for fusion is a determinant for virulence: restriction of fusion to a more acidic pH was associated with attenuation for the variant tr25 which had a shift of the threshold for maximal fusion from pH 6.30 (for the parental strain) to pH 6.00; conversely, two field strains which had maximal fusion at pH 6.60 were the most virulent.


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