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Heparan sulfate as a receptor for poxvirus infections and as a target for antiviral agents

Khanna, Mayank; Ranasinghe, Charani; Jackson, Ronald; Parish, Christopher

Description

To establish the importance of virus–heparan sulfate (HS) interactions in virus infectivity, the poxvirus vaccinia virus (VACV) was used, as it binds HS and has both enveloped virus (EV) and non-enveloped mature virus (MV) forms. Initial studies showed that heparin inhibited plaque formation by both MV-rich WR and EV-rich IHD-J strains of VACV, with the EV-rich strain also losing trademark ‘comet’-shaped plaques. However, using GFP-tagged EV and MV forms of VACV, based on IC50 values, heparin...[Show more]

dc.contributor.authorKhanna, Mayank
dc.contributor.authorRanasinghe, Charani
dc.contributor.authorJackson, Ronald
dc.contributor.authorParish, Christopher
dc.date.accessioned2021-07-01T04:29:14Z
dc.identifier.issn0022-1317
dc.identifier.urihttp://hdl.handle.net/1885/238495
dc.description.abstractTo establish the importance of virus–heparan sulfate (HS) interactions in virus infectivity, the poxvirus vaccinia virus (VACV) was used, as it binds HS and has both enveloped virus (EV) and non-enveloped mature virus (MV) forms. Initial studies showed that heparin inhibited plaque formation by both MV-rich WR and EV-rich IHD-J strains of VACV, with the EV-rich strain also losing trademark ‘comet’-shaped plaques. However, using GFP-tagged EV and MV forms of VACV, based on IC50 values, heparin was 16-fold more effective at inhibiting the infectivity of the EV form compared to the MV form. Furthermore, 6-O and N-sulfation of the glucosamine residues of heparin was essential for inhibition of the infectivity of both VACV forms. Several low-molecular-weight HS mimetics were also shown to have substantial antiviral activity, with glycosidic linkages, chain length and monosaccharide backbone being important contributors towards anti-VACV activity. In fact, the d -mannose-based sulfated oligosaccharide mixture, PI-88 (Muparfostat), was four-fold more active than heparin at inhibiting MV infections. Paradoxically, despite heparin and HS mimetics being potent inhibitors of VACV infections, removal of HS from cell surfaces by enzymatic or genetic means resulted in only a modest reduction in infectivity. It is unlikely that this paradox can be explained by steric hindrance, due to the low molecular weight of the HS mimetics (~1–2.5 kDa), with a more likely explanation being that binding of heparin/HS mimetics to free VACV initiates an abortive viral infection. Based on this explanation, HS mimetics have considerable potential as antivirals against HS-binding viruses.
dc.description.sponsorshipC. R. P. was funded by a National Health and Medical Research Council (NHMRC) programme grant.
dc.format.mimetypeapplication/pdf
dc.language.isoen_AU
dc.publisherSociety for General Microbiology
dc.rights© 2017 The Authors
dc.sourceJournal of General Virology
dc.titleHeparan sulfate as a receptor for poxvirus infections and as a target for antiviral agents
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume98
dc.date.issued2017
local.identifier.absfor110703 - Autoimmunity
local.identifier.absfor110799 - Immunology not elsewhere classified
local.identifier.ariespublicationu4351680xPUB281
local.publisher.urlhttps://www.microbiologyresearch.org/content/journal/jgv
local.type.statusAccepted Version
local.contributor.affiliationKhanna, Mayank, College of Health and Medicine, ANU
local.contributor.affiliationRanasinghe, Charani, College of Health and Medicine, ANU
local.contributor.affiliationJackson, Ronald, College of Health and Medicine, ANU
local.contributor.affiliationParish, Christopher, College of Health and Medicine, ANU
local.bibliographicCitation.issue10
local.bibliographicCitation.startpage2556
local.bibliographicCitation.lastpage2568
local.identifier.doi10.1099/jgv.0.000921
local.identifier.absseo920109 - Infectious Diseases
dc.date.updated2020-11-23T10:37:08Z
local.identifier.scopusID2-s2.0-85030987788
local.identifier.thomsonIDMEDLINE:28933686
dcterms.accessRightsOpen Access
dc.provenancehttps://v2.sherpa.ac.uk/id/publication/14639..."The Accepted Version can be archived in a Non-Commercial Institutional Repository" from SHERPA/RoMEO site (as at 18/08/2021). © 2017 The Authors. The definitive peer reviewed, edited version of this article is published in [Khanna, Mayank, et al. "Heparan sulfate as a receptor for poxvirus infections and as a target for antiviral agents." Journal of General Virology 98.10 (2017): 2556-2568., 10.1099/jgv.0.000921]
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