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dc.contributor.author
Brandenberg, Oliver F.
dc.contributor.author
Rusert, Peter
dc.contributor.author
Magnus, Carsten
dc.contributor.author
Weber, Jacqueline
dc.contributor.author
Böni, Jürg
dc.contributor.author
Günthard, Huldrych E.
dc.contributor.author
Regoes, Roland R.
dc.contributor.author
Trkola, Alexandra
dc.date.accessioned
2019-05-13T14:52:12Z
dc.date.available
2017-06-11T13:14:36Z
dc.date.available
2019-05-13T14:52:12Z
dc.date.issued
2014
dc.identifier.issn
1742-4690
dc.identifier.other
10.1186/s12977-014-0075-y
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/91296
dc.identifier.doi
10.3929/ethz-b-000091296
dc.description.abstract
Background Variable loops 1 and 2 (V1V2) of the HIV-1 envelope glycoprotein gp120 perform two key functions: ensuring envelope trimer entry competence and shielding against neutralizing antibodies. While preserving entry functionality would suggest a high need for V1V2 sequence optimization and conservation, shielding efficacy is known to depend on a high flexibility of V1V2 giving rise to its substantial sequence variability. How entry competence of the trimer is maintained despite the continuous emergence of antibody escape mutations within V1V2 has not been resolved. Since HIV cell-cell transmission is considered a highly effective means of virus dissemination, we investigated whether cell-cell transmission may serve to enhance infectivity of V1V2 variants with debilitated free virus entry. Results In a detailed comparison of wt and V1V2 mutant envelopes, V1V2 proved to be a key factor in ascertaining free virus infectivity, with V1V2 mutants displaying significantly reduced trimer integrity. Despite these defects, cell-cell transmission was able to partially rescue infectivity of V1V2 mutant viruses. We identified two regions, encompassing amino acids 156 to 160 (targeted by broadly neutralizing antibodies) and 175 to 180 (encompassing the α4β7 binding site) which were particularly prone to free virus infectivity loss upon mutation but maintained infectivity in cell-cell transmission. Of note, V1V2 antibody shielding proved important during both free virus infection and cell-cell transmission. Conclusions Based on our data we propose a model for V1V2 evolution that centers on cell-cell transmission as a salvage pathway for virus replication. Escape from antibody neutralization may frequently result in V1V2 mutations that reduce free virus infectivity. Cell-cell transmission could provide these escape viruses with sufficiently high replication levels that enable selection of compensatory mutations, thereby restoring free virus infectivity while ensuring antibody escape. Thus, our study highlights the need to factor in cell-cell transmission when considering neutralization escape pathways of HIV-1.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
BioMed Central
en_US
dc.rights.uri
http://creativecommons.org/licenses/by/4.0/
dc.subject
HIV
en_US
dc.subject
Cell-cell transmission
en_US
dc.subject
V1V2
en_US
dc.subject
Entry
en_US
dc.subject
Neutralization
en_US
dc.subject
Antibody escape
en_US
dc.title
Partial rescue of V1V2 mutant infectivity by HIV-1 cell-cell transmission supports the domain’s exceptional capacity for sequence variation
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution 4.0 International
dc.date.published
2014-09-25
ethz.journal.title
Retrovirology
ethz.journal.volume
11
en_US
ethz.journal.abbreviated
Retrovirology
ethz.pages.start
75
en_US
ethz.size
22 p.
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.identifier.nebis
010201007
ethz.publication.place
London
en_US
ethz.publication.status
published
en_US
ethz.date.deposited
2017-06-11T13:14:45Z
ethz.source
ECIT
ethz.identifier.importid
imp59365271b1de193644
ethz.ecitpid
pub:143649
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2017-07-15T03:43:01Z
ethz.rosetta.lastUpdated
2019-05-13T14:52:23Z
ethz.rosetta.exportRequired
true
ethz.rosetta.versionExported
true
ethz.COinS
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