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Deliberate Attenuation of Chikungunya Virus by Adaptation to Heparan Sulfate-Dependent Infectivity: A Model for Rational Arboviral Vaccine Design

Gardner, CL and Hritz, J and Sun, C and Vanlandingham, DL and Song, TY and Ghedin, E and Higgs, S and Klimstra, WB and Ryman, KD (2014) Deliberate Attenuation of Chikungunya Virus by Adaptation to Heparan Sulfate-Dependent Infectivity: A Model for Rational Arboviral Vaccine Design. PLoS Neglected Tropical Diseases, 8 (2). ISSN 1935-2727

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Abstract

Mosquito-borne chikungunya virus (CHIKV) is a positive-sense, single-stranded RNA virus from the genus Alphavirus, family Togaviridae, which causes fever, rash and severe persistent polyarthralgia in humans. Since there are currently no FDA licensed vaccines or antiviral therapies for CHIKV, the development of vaccine candidates 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, and 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 candidate, 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 and comparisons of the mutant viruses revealed surface exposure of the mutated residue on the spike and 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 candidate for inclusion in a CHIKV LAV. © 2014 Gardner et al.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Gardner, CLclg50@pitt.eduCLG50
Hritz, J
Sun, Cchs79@pitt.eduCHS79
Vanlandingham, DL
Song, TYtis28@pitt.eduTIS28
Ghedin, Eelg21@pitt.eduELG21
Higgs, S
Klimstra, WBklimstra@pitt.eduKLIMSTRA
Ryman, KDryman@pitt.eduRYMAN
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorWeaver, Scott C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Centers: Other Centers, Institutes, or Units > Center for Vaccine Research
Date: 1 January 2014
Date Type: Publication
Journal or Publication Title: PLoS Neglected Tropical Diseases
Volume: 8
Number: 2
DOI or Unique Handle: 10.1371/journal.pntd.0002719
Schools and Programs: School of Medicine > Computational and Systems Biology
School of Medicine > Microbiology and Molecular Genetics
Refereed: Yes
ISSN: 1935-2727
Date Deposited: 23 Jun 2014 21:36
Last Modified: 05 Feb 2019 00:55
URI: http://d-scholarship.pitt.edu/id/eprint/21914

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