| Autor: |
Duke ER; Fred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Division, Seattle, WA 98109, USA.; Department of Medicine, University of Washington, Seattle, WA 98195, USA., Boshier FAT; Fred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Division, Seattle, WA 98109, USA.; Department of Infection, Immunity and Inflammation, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK., Boeckh M; Fred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Division, Seattle, WA 98109, USA.; Department of Medicine, University of Washington, Seattle, WA 98195, USA., Schiffer JT; Fred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Division, Seattle, WA 98109, USA.; Department of Medicine, University of Washington, Seattle, WA 98195, USA., Cardozo-Ojeda EF; Fred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Division, Seattle, WA 98109, USA. |
| Abstrakt: |
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. |
