Superinfection interference of alpha and orthoflavivirus pathogens by homologous non-pathogenic vaccine strains

We have developed host-restricted, live attenuated virus (HR-LAV) vaccine strains of six tropical disease pathogens (chikungunya and dengue 1-4) that are non-pathogenic in vertebrates. The HR-LAV vaccine strains replicate efficiently in insect cells but are severely impaired in their replication within vertebrate cells, and the large deletions in these vaccine strains effectively prevent reversion to the wild type (WT) in the restrictive host. Here, we describe a novel approach that uses these homologous, but non-pathogenic HR-LAV vaccine strains to disrupt replication of secondary infections of WT pathogenic virus through the mechanism of Superinfection Exclusion, an intrinsic insect mechanism of virus replication control. Our results demonstrate that persistent primary infections of HR-LAV strains show a significant degree of pathogen interference in several mosquito cell lines, which may also be used to limit replication of WT virus in the whole mosquito.IMPORTANCEWe describe experiments that suggest a theoretical approach for mitigating the spread of mosquito-vectored diseases of medical importance. This method would exploit the phenomenon of superinfection exclusion, in which the presence of a virus in a cell prevents the expression of a second infecting virus. These data suggest that further studies in live insects are merited. Such studies may reveal that this method may be employed to replace the current mosquito control technologies that are environmentally unfriendly and harmful to humans, animals, and other insects that are important to the ecosystem.