Computational modeling of protracted HCMV replication using genome substrates and protein temporal profiles. Proc Natl Acad Sci U S A 2022 Aug 30;119(35):e2201787119
Date
08/23/2022Pubmed ID
35994667Pubmed Central ID
PMC9437303DOI
10.1073/pnas.2201787119Scopus ID
2-s2.0-85136192098 (requires institutional sign-in at Scopus site) 2 CitationsAbstract
Human cytomegalovirus (HCMV) is a major cause of illness in immunocompromised individuals. The HCMV lytic cycle contributes to the clinical manifestations of infection. The lytic cycle occurs over ∼96 h in diverse cell types and consists of viral DNA (vDNA) genome replication and temporally distinct expression of hundreds of viral proteins. Given its complexity, understanding this elaborate system can be facilitated by the introduction of mechanistic computational modeling of temporal relationships. Therefore, we developed a multiplicity of infection (MOI)-dependent mechanistic computational model that simulates vDNA kinetics and late lytic replication based on in-house experimental data. The predictive capabilities were established by comparison to post hoc experimental data. Computational analysis of combinatorial regulatory mechanisms suggests increasing rates of protein degradation in association with increasing vDNA levels. The model framework also allows expansion to account for additional mechanisms regulating the processes. Simulating vDNA kinetics and the late lytic cycle for a wide range of MOIs yielded several unique observations. These include the presence of saturation behavior at high MOIs, inefficient replication at low MOIs, and a precise range of MOIs in which virus is maximized within a cell type, being 0.382 IU to 0.688 IU per fibroblast. The predicted saturation kinetics at high MOIs are likely related to the physical limitations of cellular machinery, while inefficient replication at low MOIs may indicate a minimum input material required to facilitate infection. In summary, we have developed and demonstrated the utility of a data-driven and expandable computational model simulating lytic HCMV infection.
Author List
Monti CE, Mokry RL, Schumacher ML, Dash RK, Terhune SSAuthors
Ranjan K. Dash PhD Professor in the Biomedical Engineering department at Medical College of WisconsinScott Terhune PhD Professor in the Microbiology and Immunology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Computer SimulationCytomegalovirus
DNA, Viral
Fibroblasts
Genome, Viral
Humans
Kinetics
Time Factors
Viral Proteins
Virus Replication
