Koennyu, B;
Sadiq, SK;
Turanyi, T;
Hirmondo, R;
Mueller, B;
Kraeusslich, H-G;
Coveney, PV;
(2013)
Gag-Pol Processing during HIV-1 Virion Maturation: A Systems Biology Approach.
PLOS Computational Biology
, 9
(6)
, Article e1003103. 10.1371/journal.pcbi.1003103.
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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.
| Type: | Article |
|---|---|
| Title: | Gag-Pol Processing during HIV-1 Virion Maturation: A Systems Biology Approach |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.pcbi.1003103 |
| Publisher version: | http://dx.doi.org/10.1371/journal.pcbi.1003103 |
| Language: | English |
| Additional information: | © 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. PubMed ID: 23754941 |
| Keywords: | Data processing, drug interactions, enzymes, HIV-1, organism development, proteases, viral packaging, virions |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1418287 |
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