Novel decay dynamics revealed for virus-mediated drug activation in cytomegalovirus infection

Rose, J., Emery, V. C., Kumar, D., Asberg, A., Hartmann, A., Jardine, A. G. , Bignamini, A. A., Humar, A. and Neumann, A. U. (2017) Novel decay dynamics revealed for virus-mediated drug activation in cytomegalovirus infection. PLoS Pathogens, 13(4), e1006299. (doi: 10.1371/journal.ppat.1006299) (PMID:28406982) (PMCID:PMC5391089)

[img]
Preview
Text
139138.pdf - Published Version
Available under License Creative Commons Attribution.

1MB

Abstract

Human cytomegalovirus (CMV) infection is a substantial cause of morbidity and mortality in immunocompromised hosts and globally is one of the most important congenital infections. The nucleoside analogue ganciclovir (GCV), which requires initial phosphorylation by the viral UL97 kinase, is the mainstay for treatment. To date, CMV decay kinetics during GCV therapy have not been extensively investigated and its clinical implications not fully appreciated. We measured CMV DNA levels in the blood of 92 solid organ transplant recipients with CMV disease over the initial 21 days of ganciclovir therapy and identified four distinct decay patterns, including a new pattern exhibiting a transient viral rebound (Hump) following initial decline. Since current viral dynamics models were unable to account for this Hump profile, we developed a novel multi-level model, which includes the intracellular role of UL97 in the continued activation of ganciclovir, that successfully described all the decline patterns observed. Fitting the data allowed us to estimate ganciclovir effectiveness in vivo (mean 92%), infected cell half-life (mean 0.7 days), and other viral dynamics parameters that determine which of the four kinetic patterns will ensue. An important clinical implication of our results is that the virological efficacy of GCV operates over a broad dose range. The model also raises the possibility that GCV can drive replication to a new lower steady state but ultimately cannot fully eradicate it. This model is likely to be generalizable to other anti-CMV nucleoside analogs that require activation by viral enzymes such as UL97 or its homologues.

Item Type:Articles
Additional Information:Funded by Wellcome Trust (GB) (www.wellcome.a.uk) G078332, The MRC (UK) (www.mrc.ac.uk) G0900950 and an unrestrictive grant from Hoffman-La-Roche (www.roche.com).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Jardine, Professor Alan
Authors: Rose, J., Emery, V. C., Kumar, D., Asberg, A., Hartmann, A., Jardine, A. G., Bignamini, A. A., Humar, A., and Neumann, A. U.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:PLoS Pathogens
Publisher:Public Library of Science
ISSN:1553-7366
ISSN (Online):1553-7374
Copyright Holders:Copyright © 2017 Rose et al
First Published:First published in PLoS Pathogens 13(4): e1006299
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record