Design of chimeric alphaviruses with a programmed, attenuated, cell type-restricted phenotype

Dal Young Kim, Svetlana Atasheva, Niall J. Foy, Eryu Wang, Elena I. Frolova, Scott Weaver, Ilya Frolov

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

The Alphavirus genus in the Togaviridae family contains a number of human and animal pathogens. The importance of alphaviruses has been strongly underappreciated; however, epidemics of chikungunya virus (CHIKV), causing millions of cases of severe and 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 and 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 and, in contrast to naturally circulating viruses, lacked the important contributors to viral pathogenesis: genes encoding proteins functioning in inhibition of cellular transcription and downregulation of the cellular antiviral response. To make these viruses incapable of transmission by mosquito vectors and 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 and produced variants which (i) demonstrated different levels of replication and 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, and (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.

Original languageEnglish (US)
Pages (from-to)4363-4376
Number of pages14
JournalJournal of Virology
Volume85
Issue number9
DOIs
StatePublished - May 2011

Fingerprint

Alphavirus
Phenotype
phenotype
Chikungunya virus
Viruses
viruses
structural proteins
Antiviral Agents
Alphavirus Infections
cells
Togaviridae
Genome
Culicidae
Viral Structural Proteins
Proteins
Vero Cells
Viral Genes
RNA Viruses
animal pathogens
Virus Replication

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Kim, D. Y., Atasheva, S., Foy, N. J., Wang, E., Frolova, E. I., Weaver, S., & Frolov, I. (2011). Design of chimeric alphaviruses with a programmed, attenuated, cell type-restricted phenotype. Journal of Virology, 85(9), 4363-4376. https://doi.org/10.1128/JVI.00065-11

Design of chimeric alphaviruses with a programmed, attenuated, cell type-restricted phenotype. / Kim, Dal Young; Atasheva, Svetlana; Foy, Niall J.; Wang, Eryu; Frolova, Elena I.; Weaver, Scott; Frolov, Ilya.

In: Journal of Virology, Vol. 85, No. 9, 05.2011, p. 4363-4376.

Research output: Contribution to journalArticle

Kim, DY, Atasheva, S, Foy, NJ, Wang, E, Frolova, EI, Weaver, S & Frolov, I 2011, 'Design of chimeric alphaviruses with a programmed, attenuated, cell type-restricted phenotype', Journal of Virology, vol. 85, no. 9, pp. 4363-4376. https://doi.org/10.1128/JVI.00065-11
Kim, Dal Young ; Atasheva, Svetlana ; Foy, Niall J. ; Wang, Eryu ; Frolova, Elena I. ; Weaver, Scott ; Frolov, Ilya. / Design of chimeric alphaviruses with a programmed, attenuated, cell type-restricted phenotype. In: Journal of Virology. 2011 ; Vol. 85, No. 9. pp. 4363-4376.
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