Novel decay dynamics revealed for virus-mediated drug activation in cytomegalovirus infection.
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 mains...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2017-04-01
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| Series: | PLoS Pathogens |
| Online Access: | http://europepmc.org/articles/PMC5391089?pdf=render |
| _version_ | 1811226259785515008 |
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| author | Jessica Rose Vincent C Emery Deepali Kumar Anders Asberg Anders Hartmann Alan G Jardine Angelo A Bignamini Atul Humar Avidan U Neumann |
| author_facet | Jessica Rose Vincent C Emery Deepali Kumar Anders Asberg Anders Hartmann Alan G Jardine Angelo A Bignamini Atul Humar Avidan U Neumann |
| author_sort | Jessica Rose |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T09:22:06Z |
| format | Article |
| id | doaj.art-f6b9032720764cdb8f7975987e25128a |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-04-12T09:22:06Z |
| publishDate | 2017-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-f6b9032720764cdb8f7975987e25128a2022-12-22T03:38:37ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742017-04-01134e100629910.1371/journal.ppat.1006299Novel decay dynamics revealed for virus-mediated drug activation in cytomegalovirus infection.Jessica RoseVincent C EmeryDeepali KumarAnders AsbergAnders HartmannAlan G JardineAngelo A BignaminiAtul HumarAvidan U NeumannHuman 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.http://europepmc.org/articles/PMC5391089?pdf=render |
| spellingShingle | Jessica Rose Vincent C Emery Deepali Kumar Anders Asberg Anders Hartmann Alan G Jardine Angelo A Bignamini Atul Humar Avidan U Neumann Novel decay dynamics revealed for virus-mediated drug activation in cytomegalovirus infection. PLoS Pathogens |
| title | Novel decay dynamics revealed for virus-mediated drug activation in cytomegalovirus infection. |
| title_full | Novel decay dynamics revealed for virus-mediated drug activation in cytomegalovirus infection. |
| title_fullStr | Novel decay dynamics revealed for virus-mediated drug activation in cytomegalovirus infection. |
| title_full_unstemmed | Novel decay dynamics revealed for virus-mediated drug activation in cytomegalovirus infection. |
| title_short | Novel decay dynamics revealed for virus-mediated drug activation in cytomegalovirus infection. |
| title_sort | novel decay dynamics revealed for virus mediated drug activation in cytomegalovirus infection |
| url | http://europepmc.org/articles/PMC5391089?pdf=render |
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