Mathematical Modeling of Rhesus Cytomegalovirus (RhCMV) Placental Transmission in Seronegative Rhesus Macaques

Abstract

Approximately 1 in 200 infants is born with congenital cytomegalovirus (CMV), making it the most common congenital infection. About 1 in 5 congenitally-infected babies will suffer long-term sequelae, including sensorineural deafness, intellectual disability, and epilepsy. CMV infection is highly species-dependent, and the Rhesus CMV (RhCMV) infection of rhesus monkey fetuses is the only animal model that replicates essential features of congenital CMV infection in humans, including placental transmission, fetal disease, and fetal loss. To better understand the determinants and dynamics of congenital CMV transmission, we developed a mathematical model for placental transmission, comprising of maternal, placental, and fetal compartments using parameters from literature and experimental data from RhCMV seronegative rhesus macaques inoculated with RhCMV at 7.7-9.0 weeks of pregnancy. The model was then used to study the effect of the timing of inoculation, maternal immune suppression, and hyper-immune globulin infusion on the risk of placental transmission in the context of primary and reactivated chronic maternal CMV infection. Author summaryCongenital cytomegalovirus (CMV) is the most common congenital infection in humans. Congenial CMV affects 1 in 200 infants, and can result in sensorineural deafness, intellectual disability, epilepsy, and death. The Rhesus CMV (RhCMV) model is the only animal model that replicates essential features of congenital CMV infection and fetal sequelae in humans and provides a critical experimental system to develop mechanistic insight. We propose a novel mathematical model for CMV transmission that integrates viral dynamics in the maternal, placental, and fetal compartments. We calibrate the model using data from RhCMV transmission experiments and show that the model can recapitulate experimental observations of primary versus reactivated chronic CMV infection in pregnancy, primary infection at different stages in pregnancy, and infection in the presence of varying degrees of immune suppression and hyper-immune globulin infusion. Our in-silico model provides a means to rapidly explore mechanistic hypotheses for the physical, viral, and immune determinants of CMV transmission to complement and support expensive and difficult experiments on non-human primates.