Investigating the consequences of interference between multiple CD8+ T cell escape mutations in early HIV infection

Garcia, Victor; Feldman, Marcus W.; Regoes, Roland R.

doi:10.21256/zhaw-4703

Please use this identifier to cite or link to this item: https://doi.org/10.21256/zhaw-4703

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DC Field	Value	Language
dc.contributor.author	Garcia, Victor	-
dc.contributor.author	Feldman, Marcus W.	-
dc.contributor.author	Regoes, Roland R.	-
dc.date.accessioned	2018-09-13T06:18:23Z	-
dc.date.available	2018-09-13T06:18:23Z	-
dc.date.issued	2016-02	-
dc.identifier.issn	1553-7358	de_CH
dc.identifier.issn	1553-7358	de_CH
dc.identifier.uri	https://digitalcollection.zhaw.ch/handle/11475/10498	-
dc.description.abstract	During 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.iso	en	de_CH
dc.publisher	Public Library of Science	de_CH
dc.relation.ispartof	PLOS Computational Biology	de_CH
dc.rights	http://creativecommons.org/licenses/by/4.0/	de_CH
dc.subject	CD8+ T-Lymphocytes	de_CH
dc.subject	Computational biology	de_CH
dc.subject	Epitopes, T-Lymphocyte	de_CH
dc.subject	Molecular evolution	de_CH
dc.subject	HIV infections	de_CH
dc.subject	HIV-1	de_CH
dc.subject	Humans	de_CH
dc.subject	Immune evasion	de_CH
dc.subject.ddc	571: Physiologie und verwandte Themen	de_CH
dc.title	Investigating the consequences of interference between multiple CD8+ T cell escape mutations in early HIV infection	de_CH
dc.type	Beitrag in wissenschaftlicher Zeitschrift	de_CH
dcterms.type	Text	de_CH
zhaw.departement	Life Sciences und Facility Management	de_CH
zhaw.organisationalunit	Institut für Computational Life Sciences (ICLS)	de_CH
dc.identifier.doi	10.21256/zhaw-4703	-
dc.identifier.doi	10.1371/journal.pcbi.1004721	de_CH
dc.identifier.pmid	26829720	de_CH
zhaw.funding.eu	No	de_CH
zhaw.issue	2	de_CH
zhaw.originated.zhaw	No	de_CH
zhaw.pages.end	23	de_CH
zhaw.pages.start	1	de_CH
zhaw.publication.status	publishedVersion	de_CH
zhaw.volume	12	de_CH
zhaw.publication.review	Peer review (Publikation)	de_CH
zhaw.funding.snf	P2EZP3_162257	de_CH
zhaw.webfeed	Applied Mathematical Biology	de_CH
Appears in collections:	Publikationen Life Sciences und Facility Management

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Garcia, V., Feldman, M. W., & Regoes, R. R. (2016). Investigating the consequences of interference between multiple CD8+ T cell escape mutations in early HIV infection. PLOS Computational Biology, 12(2), 1–23. https://doi.org/10.21256/zhaw-4703

Garcia, V., Feldman, M.W. and Regoes, R.R. (2016) ‘Investigating the consequences of interference between multiple CD8+ T cell escape mutations in early HIV infection’, PLOS Computational Biology, 12(2), pp. 1–23. Available at: https://doi.org/10.21256/zhaw-4703.

V. Garcia, M. W. Feldman, and R. R. Regoes, “Investigating the consequences of interference between multiple CD8+ T cell escape mutations in early HIV infection,” PLOS Computational Biology, vol. 12, no. 2, pp. 1–23, Feb. 2016, doi: 10.21256/zhaw-4703.

GARCIA, Victor, Marcus W. FELDMAN und Roland R. REGOES, 2016. Investigating the consequences of interference between multiple CD8+ T cell escape mutations in early HIV infection. PLOS Computational Biology. Februar 2016. Bd. 12, Nr. 2, S. 1–23. DOI 10.21256/zhaw-4703

Garcia, Victor, Marcus W. Feldman, and Roland R. Regoes. 2016. “Investigating the Consequences of Interference between Multiple CD8+ T Cell Escape Mutations in Early HIV Infection.” PLOS Computational Biology 12 (2): 1–23. https://doi.org/10.21256/zhaw-4703.

Garcia, Victor, et al. “Investigating the Consequences of Interference between Multiple CD8+ T Cell Escape Mutations in Early HIV Infection.” PLOS Computational Biology, vol. 12, no. 2, Feb. 2016, pp. 1–23, https://doi.org/10.21256/zhaw-4703.