We have genetically engineered an attenuated yellow fever (YF) virus to carry and express foreign antigenic sequences and evaluated the potential of this type of recombinant virus to serve as a safe and effective tumor vaccine. Live-attenuated YF vaccine is one of the most effective viral vaccines available today. Important advantages include its ability to induce long-lasting immunity, its safety, its affordability, and its documented efficacy. In this study, recombinant live-attenuated (strain 17D) YF viruses were constructed to express a cytotoxic T-lymphocyte epitope derived from chicken ovalbumin (SIINFEKL). Yellow fever (YF) virus 17D is an extremely safe and effective live viral vaccine, prepared from infected chicken embryos under standards developed by the World Health Organization. After vaccination, immunity is elicited within 10 days in over 95% of vaccinees (42) and neutralizing antibodies directed against the virus can be detected for more than 35 years (40). The vaccine safety record is outstanding: serious adverse reactions to YF virus 17D vaccine are extremely uncommon, and reversion to wild type is virtually nonexistent (4, 52).YF virus is an enveloped, positive-stranded RNA virus and a member of the Flavivirus genus within the family Flaviviridae.

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The DA strain of Theiler's virus causes, in susceptible strains of mice, a persistent infection of the white matter of the spinal cord accompanied by chronic inflammation and primary demyelination. In resistant strains, including all H-2 b strains, mice clear the infection after 1 to 2 weeks. We inoculated RHA␤ o/o mice, an H-2 b strain which does not express class II molecules. We found that they are susceptible to persistent infection and that they develop foci of chronic inflammation with demyelination. However, these foci are smaller and contain fewer demyelinated axons than those observed in susceptible SJL/J or ␤2m ؊/؊ mice.

Theiler's virus persists in the white matter of the spinal cord of genetically susceptible mice and causes primary demyelination. The virus persists in macrophages/microglial cells, but also in oligodendrocytes, the myelin-forming cells. Susceptibility/resistance to this chronic infection has been mapped to several loci including one tentatively located in the telomeric region of chromosome 18, close to the myelin basic protein locus (Mbp locus). To determine if the MBP gene influences viral persistence, we inoculated C3H mice bearing the shiverer mutation, a 20-kb deletion in the gene. Whereas control C3H mice were of intermediate susceptibility, C3H mice heterozygous for the mutation were very susceptible, and those homozygous for the mutation were completely resistant. This resistance was not immune mediated. Furthermore, C3H/101H mice homozygous for a point mutation in the gene coding for the proteolipid protein of myelin, the rumpshaker mutation, were resistant. These results strongly support the view that oligodendrocytes are a necessary viral target for the establishment of a persistent infection by Theiler's virus.