Autor(es): Gardner Christina L, Hritz Jozef, Sun Chengqun, Vanlandingham Dana L, Song Timothy Y, Ghedin Elodie, Higgs Stephen, Klimstra William B, Ryman Kate D

Resumo: Mosquito-borne chikungunya virus (CHIKV) is a positive-sense, single-str-ed RNA virus from the genus Alphavirus, family Togaviridae, which causes fever, rash - severe persistent polyarthralgia in humans. Since there are currently no FDA licensed vaccines or antiviral therapies for CHIKV, the development of vaccine c-idates is of critical importance. Historically, live-attenuated vaccines (LAVs) for protection against arthropod-borne viruses have been created by blind cell culture passage leading to attenuation of disease, while maintaining immunogenicity. Attenuation may occur via multiple mechanisms. However, all examined arbovirus LAVs have in common the acquisition of positively charged amino acid substitutions in cell-surface attachment proteins that render virus infection partially dependent upon heparan sulfate (HS), a ubiquitously expressed sulfated polysaccharide, - appear to attenuate by retarding dissemination of virus particles in vivo. We previously reported that, like other wild-type Old World alphaviruses, CHIKV strain, La Réunion, (CHIKV-LR), does not depend upon HS for infectivity. To deliberately identify CHIKV attachment protein mutations that could be combined with other attenuating processes in a LAV c-idate, we passaged CHIKV-LR on evolutionarily divergent cell-types. A panel of single amino acid substitutions was identified in the E2 glycoprotein of passaged virus populations that were predicted to increase electrostatic potential. Each of these substitutions was made in the CHIKV-LR cDNA clone - comparisons of the mutant viruses revealed surface exposure of the mutated residue on the spike - sensitivity to competition with the HS analog, heparin, to be primary correlates of attenuation in vivo. Furthermore, we have identified a mutation at E2 position 79 as a promising c-idate for inclusion in a CHIKV LAV.

Imprenta: PLoS Neglected Tropical Diseases, v. 8, n. 2, p. e2719, 2014

Identificador do objeto digital: 10.1371/journal.pntd.0002719

Descritores: Chikungunya virus - Arbovirus ; Chikungunya virus - Biosynthesis ; Chikungunya virus - Cell ; Chikungunya virus - Pathogenesis ; Chikungunya virus - Proteins ; Chikungunya virus - RNA ; Chikungunya virus - Antibodies ; Chikungunya virus - Cytokines ; Chikungunya Virus - Virus ; Chikungunya virus - Vaccine ; Chikungunya virus - Chikungunya fever ; Chikungunya virus - Immunology

Data de publicação: 2014

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