Mathematical Modeling of Within-Host, Untreated, Cytomegalovirus Infection Dynamics after Allogeneic Transplantation

Cytomegalovirus (CMV) causes significant morbidity and mortality in recipients of allogeneic hematopoietic cell transplantation (HCT). Whereas insights gained from mathematical modeling of other chronic viral infections such as HIV, hepatitis C, and herpes simplex virus-2 have aided in optimizing th...

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Autores principales:	Elizabeth R. Duke, Florencia A. T. Boshier, Michael Boeckh, Joshua T. Schiffer, E. Fabian Cardozo-Ojeda
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	CMV kinetics virus dynamics model allogeneic transplantation Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/2167d503aa2f4a6caf767800792aae40
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spelling	oai:doaj.org-article:2167d503aa2f4a6caf767800792aae402021-11-25T19:14:15ZMathematical Modeling of Within-Host, Untreated, Cytomegalovirus Infection Dynamics after Allogeneic Transplantation10.3390/v131122921999-4915https://doaj.org/article/2167d503aa2f4a6caf767800792aae402021-11-01T00:00:00Zhttps://www.mdpi.com/1999-4915/13/11/2292https://doaj.org/toc/1999-4915Cytomegalovirus (CMV) causes significant morbidity and mortality in recipients of allogeneic hematopoietic cell transplantation (HCT). Whereas insights gained from mathematical modeling of other chronic viral infections such as HIV, hepatitis C, and herpes simplex virus-2 have aided in optimizing therapy, previous CMV modeling has been hindered by a lack of comprehensive quantitative PCR viral load data from untreated episodes of viremia in HCT recipients. We performed quantitative CMV DNA PCR on stored, frozen serum samples from the placebo group of participants in a historic randomized controlled trial of ganciclovir for the early treatment of CMV infection in bone marrow transplant recipients. We developed four main ordinary differential Equation mathematical models and used model selection theory to choose between 38 competing versions of these models. Models were fit using a population, nonlinear, mixed-effects approach. We found that CMV kinetics from untreated HCT recipients are highly variable. The models that recapitulated the observed patterns most parsimoniously included explicit, dynamic immune cell compartments and did not include dynamic target cell compartments, consistent with the large number of tissue and cell types that CMV infects. In addition, in our best-fitting models, viral clearance was extremely slow, suggesting severe impairment of the immune response after HCT. Parameters from our best model correlated well with participants’ clinical risk factors and outcomes from the trial, further validating our model. Our models suggest that CMV dynamics in HCT recipients are determined by host immune response rather than target cell limitation in the absence of antiviral treatment.Elizabeth R. DukeFlorencia A. T. BoshierMichael BoeckhJoshua T. SchifferE. Fabian Cardozo-OjedaMDPI AGarticleCMV kineticsvirus dynamics modelallogeneic transplantationMicrobiologyQR1-502ENViruses, Vol 13, Iss 2292, p 2292 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	CMV kinetics virus dynamics model allogeneic transplantation Microbiology QR1-502
spellingShingle	CMV kinetics virus dynamics model allogeneic transplantation Microbiology QR1-502 Elizabeth R. Duke Florencia A. T. Boshier Michael Boeckh Joshua T. Schiffer E. Fabian Cardozo-Ojeda Mathematical Modeling of Within-Host, Untreated, Cytomegalovirus Infection Dynamics after Allogeneic Transplantation
description	Cytomegalovirus (CMV) causes significant morbidity and mortality in recipients of allogeneic hematopoietic cell transplantation (HCT). Whereas insights gained from mathematical modeling of other chronic viral infections such as HIV, hepatitis C, and herpes simplex virus-2 have aided in optimizing therapy, previous CMV modeling has been hindered by a lack of comprehensive quantitative PCR viral load data from untreated episodes of viremia in HCT recipients. We performed quantitative CMV DNA PCR on stored, frozen serum samples from the placebo group of participants in a historic randomized controlled trial of ganciclovir for the early treatment of CMV infection in bone marrow transplant recipients. We developed four main ordinary differential Equation mathematical models and used model selection theory to choose between 38 competing versions of these models. Models were fit using a population, nonlinear, mixed-effects approach. We found that CMV kinetics from untreated HCT recipients are highly variable. The models that recapitulated the observed patterns most parsimoniously included explicit, dynamic immune cell compartments and did not include dynamic target cell compartments, consistent with the large number of tissue and cell types that CMV infects. In addition, in our best-fitting models, viral clearance was extremely slow, suggesting severe impairment of the immune response after HCT. Parameters from our best model correlated well with participants’ clinical risk factors and outcomes from the trial, further validating our model. Our models suggest that CMV dynamics in HCT recipients are determined by host immune response rather than target cell limitation in the absence of antiviral treatment.
format	article
author	Elizabeth R. Duke Florencia A. T. Boshier Michael Boeckh Joshua T. Schiffer E. Fabian Cardozo-Ojeda
author_facet	Elizabeth R. Duke Florencia A. T. Boshier Michael Boeckh Joshua T. Schiffer E. Fabian Cardozo-Ojeda
author_sort	Elizabeth R. Duke
title	Mathematical Modeling of Within-Host, Untreated, Cytomegalovirus Infection Dynamics after Allogeneic Transplantation
title_short	Mathematical Modeling of Within-Host, Untreated, Cytomegalovirus Infection Dynamics after Allogeneic Transplantation
title_full	Mathematical Modeling of Within-Host, Untreated, Cytomegalovirus Infection Dynamics after Allogeneic Transplantation
title_fullStr	Mathematical Modeling of Within-Host, Untreated, Cytomegalovirus Infection Dynamics after Allogeneic Transplantation
title_full_unstemmed	Mathematical Modeling of Within-Host, Untreated, Cytomegalovirus Infection Dynamics after Allogeneic Transplantation
title_sort	mathematical modeling of within-host, untreated, cytomegalovirus infection dynamics after allogeneic transplantation
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/2167d503aa2f4a6caf767800792aae40
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Mathematical Modeling of Within-Host, Untreated, Cytomegalovirus Infection Dynamics after Allogeneic Transplantation

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