2026-04-17T06:44:19Zhttps://recercat.cat/oai/request

oai:recercat.cat:10230/591462025-12-19T22:57:34Zcom_2072_6col_2072_452952

Gag-pol processing during HIV-1 virion maturation: a systems biology approach Könnyű, Balázs Sadiq, S. Kashif Turányi, Tamás Hírmondó, Rita Müller, Barbara Kräusslich, Hans-Georg Coveney, Peter V. Müller, Viktor Virus de l'hepatitis A Enzims Monòmers 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. 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. 2024-02-19T10:09:44Z 2024-02-19T10:09:44Z 2013 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion PLOS Computational Biology. 2013 Jun 6;9(6):e1003103 info:eu-repo/grantAgreement/EC/FP7/027446 © 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. http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess Public Library of Science (PLoS)