Deliberate attenuation of chikungunya virus by adaptation to heparan sulfate-dependent infectivity: a model for rational arboviral vaccine design.
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 dev...
Published in: | PLoS Neglected Tropical Diseases |
---|---|
Main Authors: | , , , , , , , , |
Format: | Article in Journal/Newspaper |
Language: | English |
Published: |
Public Library of Science (PLoS)
2014
|
Subjects: | |
Online Access: | https://doi.org/10.1371/journal.pntd.0002719 https://doaj.org/article/bd01950fdf944de7be1a383c6be4f8b4 |
id |
ftdoajarticles:oai:doaj.org/article:bd01950fdf944de7be1a383c6be4f8b4 |
---|---|
record_format |
openpolar |
spelling |
ftdoajarticles:oai:doaj.org/article:bd01950fdf944de7be1a383c6be4f8b4 2023-05-15T15:11:57+02:00 Deliberate attenuation of chikungunya virus by adaptation to heparan sulfate-dependent infectivity: a model for rational arboviral vaccine design. Christina L Gardner Jozef Hritz Chengqun Sun Dana L Vanlandingham Timothy Y Song Elodie Ghedin Stephen Higgs William B Klimstra Kate D Ryman 2014-02-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0002719 https://doaj.org/article/bd01950fdf944de7be1a383c6be4f8b4 EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC3930508?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0002719 https://doaj.org/article/bd01950fdf944de7be1a383c6be4f8b4 PLoS Neglected Tropical Diseases, Vol 8, Iss 2, p e2719 (2014) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2014 ftdoajarticles https://doi.org/10.1371/journal.pntd.0002719 2022-12-31T02:10:15Z 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. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic The Spike ENVELOPE(-37.317,-37.317,-54.017,-54.017) PLoS Neglected Tropical Diseases 8 2 e2719 |
institution |
Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Christina L Gardner Jozef Hritz Chengqun Sun Dana L Vanlandingham Timothy Y Song Elodie Ghedin Stephen Higgs William B Klimstra Kate D Ryman Deliberate attenuation of chikungunya virus by adaptation to heparan sulfate-dependent infectivity: a model for rational arboviral vaccine design. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
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. |
format |
Article in Journal/Newspaper |
author |
Christina L Gardner Jozef Hritz Chengqun Sun Dana L Vanlandingham Timothy Y Song Elodie Ghedin Stephen Higgs William B Klimstra Kate D Ryman |
author_facet |
Christina L Gardner Jozef Hritz Chengqun Sun Dana L Vanlandingham Timothy Y Song Elodie Ghedin Stephen Higgs William B Klimstra Kate D Ryman |
author_sort |
Christina L Gardner |
title |
Deliberate attenuation of chikungunya virus by adaptation to heparan sulfate-dependent infectivity: a model for rational arboviral vaccine design. |
title_short |
Deliberate attenuation of chikungunya virus by adaptation to heparan sulfate-dependent infectivity: a model for rational arboviral vaccine design. |
title_full |
Deliberate attenuation of chikungunya virus by adaptation to heparan sulfate-dependent infectivity: a model for rational arboviral vaccine design. |
title_fullStr |
Deliberate attenuation of chikungunya virus by adaptation to heparan sulfate-dependent infectivity: a model for rational arboviral vaccine design. |
title_full_unstemmed |
Deliberate attenuation of chikungunya virus by adaptation to heparan sulfate-dependent infectivity: a model for rational arboviral vaccine design. |
title_sort |
deliberate attenuation of chikungunya virus by adaptation to heparan sulfate-dependent infectivity: a model for rational arboviral vaccine design. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2014 |
url |
https://doi.org/10.1371/journal.pntd.0002719 https://doaj.org/article/bd01950fdf944de7be1a383c6be4f8b4 |
long_lat |
ENVELOPE(-37.317,-37.317,-54.017,-54.017) |
geographic |
Arctic The Spike |
geographic_facet |
Arctic The Spike |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 8, Iss 2, p e2719 (2014) |
op_relation |
http://europepmc.org/articles/PMC3930508?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0002719 https://doaj.org/article/bd01950fdf944de7be1a383c6be4f8b4 |
op_doi |
https://doi.org/10.1371/journal.pntd.0002719 |
container_title |
PLoS Neglected Tropical Diseases |
container_volume |
8 |
container_issue |
2 |
container_start_page |
e2719 |
_version_ |
1766342723520954368 |