The research proposed has two main goals: first, to test the ability of live virus vaccines used for influenza, poliomyelitis, measles, mumps, and rubella to act as dominant-negative mutants; and second, to examine the mechanism of this dominance where it is found to occur. The ability to inhibit the growth of wild-type virus in mixed infections is a desirable trait for any live virus vaccine. This phenotype could permit the vaccine strain to block the growth of any wild-type revertants that arise during the immunization process. Dominance may also afford protection to superinfection with an external source of wild-type virus during immunization or modify a developing infection. Cell culture and animal model systems will be employed to examine the effects of coinfection with the live virus vaccines on the growth of wild-type virus. The relative yield of the two viruses will be analyzed by a variety of quantitative and qualitative techniques. Preliminary studies have established that coinfection with the cold-adapted candidate vaccine for influenza A inhibits the growth of wild-type virus by as much as three orders of magnitude. Through the use of single gene reassortants, the identity of the vaccine virus gene(s) responsible for this interference will be determined. In addition, experiments will be performed to establish the point in the growth cycle at which the interference occurs. Similar studies are planned with the other live virus vaccines that are found to interfere. It is important to note that regardless of whether all of the presently available live virus vaccines possess the dominance characteristic; this is a trait that a live virus vaccine should have. This may be of particular importance in the case of poliomyelitis, where vaccine failure due to reversion to neurovirulence remains a significant public health problem. If the current vaccines are not dominant, identification of dominant-negative lesions in other mutant polioviruses may permit the genetic engineering of vaccine viruses which possess this added safety factor.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Virology Study Section (VR)
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University of Pittsburgh
Schools of Medicine
United States
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Youngner, J S; Treanor, J J; Betts, R F et al. (1994) Effect of simultaneous administration of cold-adapted and wild-type influenza A viruses on experimental wild-type influenza infection in humans. J Clin Microbiol 32:750-4
Maloy, M L; Whitaker-Dowling, P; Youngner, J S (1994) Dominance of cold-adapted influenza A virus over wild-type viruses is at the level of RNA synthesis. Virology 205:44-50
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Whitaker-Dowling, P; Maassab, H F; Youngner, J S (1991) Dominant-negative mutants as antiviral agents: simultaneous infection with the cold-adapted live-virus vaccine for influenza A protects ferrets from disease produced by wild-type influenza A. J Infect Dis 164:1200-2
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Lancz, G; Whitaker-Dowling, P; Marsh, Y V et al. (1990) Inhibition of vesicular stomatitis virus replication in dexamethasone-treated L929 cells. Proc Soc Exp Biol Med 193:190-6
Simon, K O; Cardamone Jr, J J; Whitaker-Dowling, P A et al. (1990) Cellular mechanisms in the superinfection exclusion of vesicular stomatitis virus. Virology 177:375-9
Whitaker-Dowling, P; Lucas, W; Youngner, J S (1990) Cold-adapted vaccine strains of influenza A virus act as dominant negative mutants in mixed infections with wild-type influenza A virus. Virology 175:358-64
Jordan, J A; Whitaker-Dowling, P; Youngner, J S (1989) The L protein of a VSV mutant isolated from a persistent infection is responsible for viral interference and dominance over the wild-type. Virology 169:137-41

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