| Vesicular stomatitis virus is a prototype nonsegmented, negative-sense RNA virus that has been widely used to study common aspects of RNA virus replication. Attenuated mutants of VSV have led to important discoveries about viral function, particularly genome replication and mRNA transcription. S2 VSV is small plaque isolate of VSV initially described to be attenuated in vivo but still able to induce a robust interferon response. Detailed characterization of the attenuated VSV isolate S2 has verified that this isolate is attenuated and is able to induce a blocking antibody response in vivo. Further characterization showed that this isolate is antigenically and phylogenetically distinct from related wild-type VSV isolates. Sequencing of the virus shows that there are more than three hundred nucleotide changes from the standard VSV laboratory strain, San Juan. Characterization of the RNA products produced in S2 VSV infected cells has led to the discovery of a non-interfering subgenomic particle that is carried along with S2 VSV infection. Additionally, characterization of the attenuated phenotype showed that S2 VSV has markedly different transcription gradient when compared with San Juan VSV. S2 shows a steeper gradient of polymerase transcription than wild-type virus and a decline in total transcription after 4 hpi. As expected, this decline in active transcription leads to lower level of mRNA accumulation in S2 VSV infected cells. In a coinfection with wild-type VSV, the S2 pattern of transcription is completely dominant at all times in infection, and this altered transcription phenotype of S2 is not due to an innate cellular response, as transcription in vitro duplicates the phenotype seen in cells. S2 VSV is the first demonstrated viral mutant with a steeper gradient of transcription that is not dependent on RNA template sequence or host response. The attenuation and ability of S2 VSV to inhibit wild-type virus suggests that S2 VSV would be a good candidate vector for VSV-based vaccines. In addition, the mechanism behind the altered transcriptional profile of S2 VSV has led to new understanding of the role of the polymerase complex in the unique mechanism of transcriptional control by the nonsegmented, negative-sense RNA viruses. |
