Gag-pol processing during HIV-1 virion maturation: a systems biology approach
Mostra el registre complet Registre parcial de l'ítem
- dc.contributor.author Könnyű, Balázs
- dc.contributor.author Sadiq, S. Kashif
- dc.contributor.author Turányi, Tamás
- dc.contributor.author Hírmondó, Rita
- dc.contributor.author Müller, Barbara
- dc.contributor.author Kräusslich, Hans-Georg
- dc.contributor.author Coveney, Peter V.
- dc.contributor.author Müller, Viktor
- dc.date.accessioned 2024-02-19T10:09:44Z
- dc.date.available 2024-02-19T10:09:44Z
- dc.date.issued 2013
- dc.description.abstract Proteolytic processing of Gag and Gag-Pol polyproteins by the viral protease (PR) is crucial for the production of infectious HIV-1, and inhibitors of the viral PR are an integral part of current antiretroviral therapy. The process has several layers of complexity (multiple cleavage sites and substrates; multiple enzyme forms; PR auto-processing), which calls for a systems level approach to identify key vulnerabilities and optimal treatment strategies. Here we present the first full reaction kinetics model of proteolytic processing by HIV-1 PR, taking into account all canonical cleavage sites within Gag and Gag-Pol, intermediate products and enzyme forms, enzyme dimerization, the initial auto-cleavage of full-length Gag-Pol as well as self-cleavage of PR. The model allows us to identify the rate limiting step of virion maturation and the parameters with the strongest effect on maturation kinetics. Using the modelling framework, we predict interactions and compensatory potential between individual cleavage rates and drugs, characterize the time course of the process, explain the steep dose response curves associated with PR inhibitors and gain new insights into drug action. While the results of the model are subject to limitations arising from the simplifying assumptions used and from the uncertainties in the parameter estimates, the developed framework provides an extendable open-access platform to incorporate new data and hypotheses in the future.
- dc.description.sponsorship This work was supported by the European Commission (Virolab Project Grant 027446; www.virolab.org) and the Hungarian Scientific Research Fund (OTKA grants NF72791, K84054 and K100806; www.otka.hu). VM gratefully acknowledges a Bolyai János Research Fellowship of the Hungarian Academy of Sciences (www.mta.hu). SKS acknowledges support from a European Commission FP7 Marie Curie Intra-European Fellowship (http://ec.europa.eu/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
- dc.format.mimetype application/pdf
- dc.identifier.citation Könnyű B, Sadiq SK, Turányi T, Hírmondó R, Müller B, Kräusslich HG, et al. Gag-pol processing during HIV-1 virion maturation: a systems biology approach. PLoS Comput Biol. 2013 Jun 6;9(6):e1003103. DOI: 10.1371/journal.pcbi.1003103
- dc.identifier.doi http://dx.doi.org/10.1371/journal.pcbi.1003103
- dc.identifier.issn 1553-734X
- dc.identifier.uri http://hdl.handle.net/10230/59146
- dc.language.iso eng
- dc.publisher Public Library of Science (PLoS)
- dc.relation.ispartof PLOS Computational Biology. 2013 Jun 6;9(6):e1003103
- dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/027446
- dc.rights © 2013 Könnyű et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.rights.uri http://creativecommons.org/licenses/by/4.0/
- dc.subject.other Virus de l'hepatitis A
- dc.subject.other Enzims
- dc.subject.other Monòmers
- dc.title Gag-pol processing during HIV-1 virion maturation: a systems biology approach
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion