Repository: Freie Universität Berlin, Math Department

In vitro HIV-1 Evolution in Response to Triple Reverse Transcriptase Inhibitors & In Silico Phenotypic Analysis

Rath, B. A. and Yousef, K. P. and Katzenstein, D. K. and Shafer, R. W. and Schütte, Ch. and von Kleist, M. and Merigan, T. C. (2013) In vitro HIV-1 Evolution in Response to Triple Reverse Transcriptase Inhibitors & In Silico Phenotypic Analysis. PLoS ONE, 8 (4). e61102. ISSN 1932-6203

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Official URL: http://dx.doi.org/10.1371/journal.pone.0061102

Abstract

Background Effectiveness of ART regimens strongly depends upon complex interactions between the selective pressure of drugs and the evolution of mutations that allow or restrict drug resistance. Methods Four clinical isolates from NRTI-exposed, NNRTI-naive subjects were passaged in increasing concentrations of NVP in combination with 1 µM 3 TC and 2 µM ADV to assess selective pressures of multi-drug treatment. A novel parameter inference procedure, based on a stochastic viral growth model, was used to estimate phenotypic resistance and fitness from in vitro combination passage experiments. Results Newly developed mathematical methods estimated key phenotypic parameters of mutations arising through selective pressure exerted by 3 TC and NVP. Concentrations of 1 µM 3 TC maintained the M184V mutation, which was associated with intrinsic fitness deficits. Increasing NVP concentrations selected major NNRTI resistance mutations. The evolutionary pathway of NVP resistance was highly dependent on the viral genetic background, epistasis as well as stochasticity. Parameter estimation indicated that the previously unrecognized mutation L228Q was associated with NVP resistance in some isolates. Conclusion Serial passage of viruses in the presence of multiple drugs may resemble the selection of mutations observed among treated individuals and populations in vivo and indicate evolutionary preferences and restrictions. Phenotypic resistance estimated here “in silico” from in vitro passage experiments agreed well with previous knowledge, suggesting that the unique combination of “wet-” and “dry-lab” experimentation may improve our understanding of HIV-1 resistance evolution in the future.

Item Type:Article
Subjects:Mathematical and Computer Sciences > Statistics > Stochastic Processes
Mathematical and Computer Sciences > Mathematics > Mathematical Modelling
Biological Sciences > Genetics > Medical and Veterinary Genetics > Medical Genetics
Subjects allied to Medicine > Pharmacology
Biological Sciences > Microbiology > Virology
Divisions:Other Institutes > Matheon > A - Life Sciences
Department of Mathematics and Computer Science > Institute of Mathematics > BioComputing Group
ID Code:1178
Deposited By: Dr Max von Kleist
Deposited On:22 Nov 2012 13:10
Last Modified:03 Mar 2017 14:41

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