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Substitutions at the putative receptor-binding site of an encephalitic flavivirus alter virulence and host cell tropism and reveal a role for glycosaminoglycans in entry

Lee, Eva; Lobigs, Mario

Description

The flavivirus receptor-binding domain has been putatively assigned to a hydrophilic region (FG loop) in the envelope (E) protein. In some flaviviruses this domain harbors the integrin-binding motif Arg-Gly-Asp (RGD). One of us has shown earlier that host cell adaptation of Murray Valley encephalitis virus (MVE) can result in the selection of attenuated variants altered at E protein residue Asp390, which is part of an RGD motif. Here, a full-length, infectious cDNA clone of MVE was constructed...[Show more]

dc.contributor.authorLee, Eva
dc.contributor.authorLobigs, Mario
dc.date.accessioned2015-12-13T23:16:00Z
dc.identifier.issn0022-538X
dc.identifier.urihttp://hdl.handle.net/1885/89179
dc.description.abstractThe flavivirus receptor-binding domain has been putatively assigned to a hydrophilic region (FG loop) in the envelope (E) protein. In some flaviviruses this domain harbors the integrin-binding motif Arg-Gly-Asp (RGD). One of us has shown earlier that host cell adaptation of Murray Valley encephalitis virus (MVE) can result in the selection of attenuated variants altered at E protein residue Asp390, which is part of an RGD motif. Here, a full-length, infectious cDNA clone of MVE was constructed and employed to systematically investigate the impact of single amino acid changes at Asp390 on cell tropism, virus entry, and virulence. Each of 10 different E protein 390 mutants was viable. Three mutants (Gly390, Ala390, and His390) showed pronounced differences from an infectious clone-derived control virus in growth in mammalian and mosquito cells. The altered cell tropism correlated with (i) a difference in entry kinetics, (ii) an increased dependence on glycosaminoglycans (determined by inhibition of virus infectivity by heparin) for attachment of the three mutants to different mammalian cells, and (iii) the loss of virulence in mice. These results confirm a functional role of the FG loop in the flavivirus E protein in virus entry and suggest that encephalitic flaviviruses can enter cells via attachment to glycosaminoglycans. However, it appears that additional cell surface molecules are also used as receptors by natural isolates of MVE and that the increased dependence on glycosaminoglycans for entry results in the loss of neuroinvasiveness.
dc.publisherAmerican Society for Microbiology
dc.sourceJournal of Virology
dc.subjectKeywords: glycosaminoglycan; mutant protein; virus envelope protein; amino acid substitution; animal cell; article; binding site; Encephalitis virus; Flavivirus; molecular cloning; nonhuman; priority journal; protein analysis; protein binding; virogenesis; virus ad
dc.titleSubstitutions at the putative receptor-binding site of an encephalitic flavivirus alter virulence and host cell tropism and reveal a role for glycosaminoglycans in entry
dc.typeJournal article
local.description.notesImported from ARIES
local.description.refereedYes
local.identifier.citationvolume74
dc.date.issued2000
local.identifier.absfor110804 - Medical Virology
local.identifier.ariespublicationMigratedxPub19121
local.type.statusPublished Version
local.contributor.affiliationLee, Eva, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationLobigs, Mario, College of Medicine, Biology and Environment, ANU
local.description.embargo2037-12-31
local.bibliographicCitation.issue19
local.bibliographicCitation.startpage8867
local.bibliographicCitation.lastpage8875
local.identifier.doi10.1128/JVI.74.19.8867-8875.2000
dc.date.updated2015-12-12T08:46:10Z
local.identifier.scopusID2-s2.0-0033804366
CollectionsANU Research Publications

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