Evolution

Conservation of the elements involved in transcription and replication

A comparative analysis of rabies virus strains, rabies-related viruses, rhabdoviruses in general, and paramyxoviruses indicate that strong selective pressure has stressed the following major elements controlling the gene expression: (1) the start and stop transcription signal bordering each cistron; (2) the promoters for RNA synthesis and encapsidation at the 3' and 5' genomic ends, respectively; (3) the RNA-dependent RNA polymerase (L protein), by far the most conserved polypeptide; it exhibits six highly conserved domains separated by variable areas, a distribution in agreement with the notion of independent functions (RNA synthesis, capping, polyadenylation and phosphorylation) concatenated within the polypeptide.

An intermediate place of unsegmented negative-strand RNA virus evolution

Proteins other than the L polymerase are poorly conserved. The G protein, although maintaining limited sequences around the main glycosylation site, has varied a great deal, as might be expected for the polypeptide that mediates the first contact with the host. The N protein has also retained small sequence stretches most likely involved in direct interaction with the genomic backbone. The Ml phospho-proteins and M2 matrix proteins are highly varied, as are the untranslated genomic areas.

The G-L intergene is of particular interest because of its large size and its inability to encode substantial peptides. In the same genomic location a fish rhabdovirus (infectious hematopoietic necrosis virus or IHNV) encodes an mRNA of similar size, as do the paramyxoviruses for the HN hemagglutinin protein. The rabies G-L intergene is presumed to be a remnant gene, baptized ip for pseudogene. It places rabies virus in an intermediate position in the evolution of unsegmented negative-strand RNA viruses, between the rhabdoviruses with condensed genomes (vesicular stomatitis virus, for instance, shows the dinucleotide GA between the G and L), IHNV virus and the paramyxoviruses. The L protein homology studies independently confirm that rabies virus was closer to paramyxoviruses than to VSV.

The rabies tf/ pseudogene: the best thermometer of evolution

Since it is a nonprotein coding region highly susceptible to mutation, changes in the rabies ip pseudogene are more likely to represent the natural evolution of the virus outside any external selective pressure, and this site may therefore be a suitable target for epidemiologic studies. By use of the polymerase chain reaction (PCR) technique directly from brain samples it was shown that:

• There is up to 18% divergence in the i/> pseudogene of different vaccine strains, most of which are derived from the original Pasteur strain.

• Wild isolates from a given geographic area are clearly related, with less than 2.5% divergence.

• Wildlife isolates differ by approximately 15% from vaccine strains (but complete cross-protection by those vaccines is still achieved).

• In West Africa (Ivory Coast, Cameroon, Niger and Morocco) where vaccine failures have often been noted, there is a greater (25—40%) divergence from the vaccine strains.

• European bat isolates tend to be completely different from vaccine strains at the ip pseudogene. At the G and N gene, those known to be important in initiating the immune response, the divergence between isolates from European bats and isolates from vaccine strains is comparable to the difference vs Mokola virus (against which rabies vaccines are ineffective).

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