Design of chimeric alphaviruses with a programmed, attenuated, cell type-restricted phenotype
Autor(es): Kim Dal Young, Atasheva Svetlana, Foy Niall J, Wang Eryu, Frolova Elena I, Weaver Scott, Frolov Ilya
Resumo: The Alphavirus genus in the Togaviridae family contains a number of human - animal pathogens. The importance of alphaviruses has been strongly underappreciated; however, epidemics of chikungunya virus (CHIKV), causing millions of cases of severe - often persistent arthritis in the Indian subcontinent, have raised their profile in recent years. In spite of a continuous public health threat, to date no licensed vaccines have been developed for alphavirus infections. In this study, we have applied an accumulated knowledge about the mechanism of alphavirus replication - protein function in virus-host interactions to introduce a new approach in designing attenuated alphaviruses. These variants were constructed from genes derived from different, geographically isolated viruses. The resulting viable variants encoded CHIKV envelope -, in contrast to naturally circulating viruses, lacked the important contributors to viral pathogenesis: genes encoding proteins functioning in inhibition of cellular transcription - downregulation of the cellular antiviral response. To make these viruses incapable of transmission by mosquito vectors - to differentially regulate expression of viral structural proteins, their replication was made dependent on the internal ribosome entry sites, derived from other positive-polarity RNA (RNA(+)) viruses. The rational design of the genomes was complemented by selection procedures, which adapted viruses to replication in tissue culture - produced variants which (i) demonstrated different levels of replication - production of the individual structural proteins, (ii) efficiently induced the antiviral response in infected cells, (iii) were incapable of replication in cells of mosquito origin, - (iv) efficiently replicated in Vero cells. This modular approach to genome design is applicable for the construction of other alphaviruses with a programmed, irreversibly attenuated phenotype.
Imprenta: Journal of Virology, v. 85, n. 9, p. 4363-4376, 2011
Identificador do objeto digital: 10.1128/JVI.00065-11
Descritores: Chikungunya virus - Cell ; Chikungunya virus - Genome ; Chikungunya virus - Pathogenesis ; Chikungunya virus - Proteins ; Chikungunya virus - RNA ; Chikungunya virus - Viral infections ; Chikungunya Virus - Virus ; Chikungunya virus - Transmission ; Chikungunya virus - Vaccine ; Chikungunya virus - Epidemic ; Chikungunya virus - Public health
Data de publicação: 2011
