Please use this identifier to cite or link to this item: https://doi.org/10.21256/zhaw-4703
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dc.contributor.authorGarcia, Victor-
dc.contributor.authorFeldman, Marcus W.-
dc.contributor.authorRegoes, Roland R.-
dc.date.accessioned2018-09-13T06:18:23Z-
dc.date.available2018-09-13T06:18:23Z-
dc.date.issued2016-02-
dc.identifier.issn1553-7358de_CH
dc.identifier.issn1553-7358de_CH
dc.identifier.urihttps://digitalcollection.zhaw.ch/handle/11475/10498-
dc.description.abstractDuring early human immunodeficiency virus (HIV) infection multiple CD8+ T cell responses are elicited almost simultaneously. These responses exert strong selective pressures on different parts of HIV's genome, and select for mutations that escape recognition and are thus beneficial to the virus. Some studies reveal that the later these escape mutations emerge, the more slowly they go to fixation. This pattern of escape rate decrease(ERD) can arise by distinct mechanisms. In particular, in large populations with high beneficial mutation rates interference among different escape strains--an effect that can emerge in evolution with asexual reproduction and results in delayed fixation times of beneficial mutations compared to sexual reproduction--could significantly impact the escape rates of mutations. In this paper, we investigated how interference between these concurrent escape mutations affects their escape rates in systems with multiple epitopes, and whether it could be a source of the ERD pattern. To address these issues, we developed a multilocus Wright-Fisher model of HIV dynamics with selection, mutation and recombination, serving as a null-model for interference. We also derived an interference-free null model assuming initial neutral evolution before immune response elicitation. We found that interference between several equally selectively advantageous mutations can generate the observed ERD pattern. We also found that the number of loci, as well as recombination rates substantially affect ERD. These effects can be explained by the underexponential decline of escape rates over time. Lastly, we found that the observed ERD pattern in HIV infected individuals is consistent with both independent, interference-free mutations as well as interference effects. Our results confirm that interference effects should be considered when analyzing HIV escape mutations. The challenge in estimating escape rates and mutation-associated selective coefficients posed by interference effects cannot simply be overcome by improved sampling frequencies or sizes. This problem is a consequence of the fundamental shortcomings of current estimation techniques under interference regimes. Hence, accounting for the stochastic nature of competition between mutations demands novel estimation methodologies based on the analysis of HIV strains, rather than mutation frequencies.de_CH
dc.language.isoende_CH
dc.publisherPublic Library of Sciencede_CH
dc.relation.ispartofPLoS Computational Biologyde_CH
dc.rightshttp://creativecommons.org/licenses/by/4.0/de_CH
dc.subjectCD8+ T-Lymphocytesde_CH
dc.subjectComputational biologyde_CH
dc.subjectEpitopes, T-Lymphocytede_CH
dc.subjectMolecular evolutionde_CH
dc.subjectHIV infectionsde_CH
dc.subjectHIV-1de_CH
dc.subjectHumansde_CH
dc.subjectImmune evasionde_CH
dc.subject.ddc571: Physiologie und verwandte Themende_CH
dc.titleInvestigating the consequences of interference between multiple CD8+ T cell escape mutations in early HIV infectionde_CH
dc.typeBeitrag in wissenschaftlicher Zeitschriftde_CH
dcterms.typeTextde_CH
zhaw.departementLife Sciences und Facility Managementde_CH
zhaw.organisationalunitInstitut für Angewandte Simulation (IAS)de_CH
dc.identifier.doi10.21256/zhaw-4703-
dc.identifier.doi10.1371/journal.pcbi.1004721de_CH
dc.identifier.pmid26829720de_CH
zhaw.funding.euNode_CH
zhaw.issue2de_CH
zhaw.originated.zhawNode_CH
zhaw.pages.end23de_CH
zhaw.pages.start1de_CH
zhaw.publication.statuspublishedVersionde_CH
zhaw.volume12de_CH
zhaw.publication.reviewPeer review (Publikation)de_CH
zhaw.funding.snfP2EZP3_162257de_CH
Appears in Collections:Publikationen Life Sciences und Facility Management

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