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

Gong, Yishu; Moström, Matilda J.; Otero, Claire E.; Valencia, Sarah; Kaur, Amitinder; Permar, Sallie R.; Chan, Cliburn

doi:10.1101/2022.04.07.487583

Cited by 3 publications

(6 citation statements)

References 22 publications

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“…Importantly, the rhesus macaque model of cCMV transmission following primary RhCMV infection at the end of 1 st trimester in immunocompetent dams and utilizing the end point of virus detected in AF between 2 and 12 weeks after infection accurately modeled the epidemiology of human CMV transmission following acute infection during pregnancy, with 5 of 12 dams (41.7%) with virus detection in AF [ 3 ]. Yet, contrary to our expectations and challenging a common hypothesis in the field [ 17 , 29 ], we found that maternal plasma VL magnitude and kinetics were not significantly different between AF-positive and AF-negative immunocompetent dams. While the exact mechanism of transplacental CMV transmission has not been fully defined, the notion that more virus circulating in maternal blood leads to greater risk of transmission due to the increased interaction of CMV with the maternal-fetal interface is not supported by these results.…”

Section: Discussioncontrasting

confidence: 99%

“…We reasoned that increased virus circulation in the maternal blood should result in a greater viral load (VL) at the maternal-fetal interface, increasing the likelihood of placental infection and congenital transmission. This idea has recently been supported by mathematical modeling of vertical CMV transmission [ 17 ]. Furthermore, we hypothesized that maternal virus-specific functional antibody responses such as neutralization, antibody dependent cellular cytotoxicity (ADCC), and antibody dependent cellular phagocytosis (ADCP) are important for controlling viral replication and preventing vertical transmission, as cell-to-cell spread is a key mechanism for CMV dissemination [ 18 ], meaning that antibody functions that target both cell-free and cell-associated virus may be needed for adequate control.…”

Section: Introductionmentioning

confidence: 99%

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Relationship of maternal cytomegalovirus-specific antibody responses and viral load to vertical transmission risk following primary maternal infection in a rhesus macaque model

Otero,

Barfield,

Scheef

et al. 2023

PLoS Pathog

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Cytomegalovirus (CMV) is the most common congenital infection and cause of birth defects worldwide. Primary CMV infection during pregnancy leads to a higher frequency of congenital CMV (cCMV) than maternal re-infection, suggesting that maternal immunity confers partial protection. However, poorly understood immune correlates of protection against placental transmission contributes to the current lack of an approved vaccine to prevent cCMV. In this study, we characterized the kinetics of maternal plasma rhesus CMV (RhCMV) viral load (VL) and RhCMV-specific antibody binding and functional responses in a group of 12 immunocompetent dams with acute, primary RhCMV infection. We defined cCMV transmission as RhCMV detection in amniotic fluid (AF) by qPCR. We then leveraged a large group of past and current primary RhCMV infection studies in late-first/early-second trimester RhCMV-seronegative rhesus macaque dams, including immunocompetent (n = 15), CD4+ T cell-depleted with (n = 6) and without (n = 6) RhCMV-specific polyclonal IgG infusion before infection to evaluate differences between RhCMV AF-positive and AF-negative dams. During the first 3 weeks after infection, the magnitude of RhCMV VL in maternal plasma was higher in AF-positive dams in the combined cohort, while RhCMV glycoprotein B (gB)- and pentamer-specific binding IgG responses were lower magnitude compared to AF-negative dams. However, these observed differences were driven by the CD4+ T cell-depleted dams, as there were no differences in plasma VL or antibody responses between immunocompetent AF-positive vs AF-negative dams. Overall, these results suggest that levels of neither maternal plasma viremia nor humoral responses are associated with cCMV following primary maternal infection in healthy individuals. We speculate that other factors related to innate immunity are more important in this context as antibody responses to acute infection likely develop too late to influence vertical transmission. Yet, pre-existing CMV glycoprotein-specific and neutralizing IgG may provide protection against cCMV following primary maternal CMV infection even in high-risk, immunocompromised settings.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Relationship of maternal cytomegalovirus-specific antibody responses and viral load to vertical transmission risk following primary maternal infection in a rhesus macaque model

Otero,

Barfield,

Scheef

et al. 2023

PLoS Pathog

Self Cite

View full text Add to dashboard Cite

show abstract

“…Importantly, the rhesus model of cCMV transmission following primary RhCMV infection at the end of 1 st trimester in immunocompetent dams and utilizing the end point of virus detected in AF fluid between 2 and 12 weeks after infection accurately modeled the epidemiology of human CMV transmission following acute infection during pregnancy, with 5 of 12 dams (41.7%) with virus detection in AF (3). Yet, contrary to our expectations and challenging a common hypothesis in the field (17,25), we found that maternal plasma VL magnitude and kinetics were not significantly different between AF-positive and AF-negative immunocompetent dams. While the exact mechanism of transplacental CMV transmission has not been fully defined, the notion that more virus circulating in maternal blood leads to greater risk of transmission due to the increased interaction of CMV with the maternal-fetal interface is not supported by these results.…”

Section: Discussioncontrasting

confidence: 70%

“…We reasoned that increased virus circulation in the maternal blood should result in a greater viral load at the maternal-fetal interface, increasing the likelihood of placental infection and congenital transmission. This idea has recently been supported by mathematical modeling of vertical CMV transmission (17). Furthermore, we hypothesized that maternal virus-specific functional antibody responses such as neutralization, antibody dependent cellular cytotoxicity (ADCC), and antibody dependent cellular phagocytosis (ADCP) are important for controlling viral replication and preventing vertical transmission, as cell-to-cell spread is a key mechanism for CMV dissemination (18), meaning that antibody functions that target both cell-free and cell-associated virus may be needed for adequate control.…”

Section: Introductionmentioning

confidence: 90%

Relationship of maternal cytomegalovirus-specific antibody responses and viral load to vertical transmission risk following primary maternal infection in a rhesus macaque model

Otero

Barfield

Scheef

et al. 2023

Preprint

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Cytomegalovirus (CMV) is the most common congenital infection and cause of birth defects worldwide. Primary CMV infection during pregnancy leads to a higher frequency of congenital CMV (cCMV) than maternal re-infection, suggesting that maternal immunity confers partial protection. However, poorly understood immune correlates of protection against placental transmission contributes to the current lack of an approved vaccine to prevent cCMV. In this study, we characterized the kinetics of maternal plasma rhesus CMV (RhCMV) viral load (VL) and RhCMV-specific antibody binding and functional responses in a group of 12 immunocompetent dams with acute, primary RhCMV infection. We defined cCMV transmission as RhCMV detection in amniotic fluid (AF) by qPCR. We then leveraged a large group of past and current primary RhCMV infection studies in late-first/early-second trimester RhCMV-seronegative rhesus macaque dams, including immunocompetent (n=15), CD4+ T cell-depleted with (n=6) and without (n=6) RhCMV-specific polyclonal IgG infusion before infection to evaluate differences between RhCMV AF-positive and AF-negative dams. During the first 3 weeks after infection, the magnitude of RhCMV VL in maternal plasma was higher in AF-positive dams in the combined cohort, while RhCMV glycoprotein B (gB)- and pentamer-specific binding IgG responses were lower magnitude compared to AF-negative dams. However, these observed differences were driven by the CD4+ T cell-depleted dams, as there were no differences in plasma VL or antibody responses between immunocompetent AF-positive vs AF-negative dams. Overall, these results suggest that levels of neither maternal plasma viremia nor humoral responses are associated with cCMV following primary maternal infection in healthy individuals. We speculate that other factors related to innate immunity are more important in this context as antibody responses to acute infection likely develop too late to influence vertical transmission. Yet, pre-existing CMV glycoprotein-specific and neutralizing IgG may provide protection against cCMV following primary maternal CMV infection even in high-risk, immunocompromised settings.

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“…While the dosing and frequency of hyperimmune globulin also differed in these studies, a positive effect was only observed in women with very early infection, pointing to the potential importance of accuracy in the dating of infection recency. Recent studies have started to explore the role that antibody responses play in CMV transmission in a rhesus macaque model 61,62 . However, data in humans is limited and often confounded by the differing risk of infection associated with primary as compared to non-primary infection 63 .…”

Section: Discussionmentioning

confidence: 99%

Discrimination of Primary and Chronic CMV Infection based on Humoral Immune Profiles in Pregnancy

Hederman,

Remmel,

Sharma

et al. 2024

Preprint

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Most humans have been infected by Cytomegalovirus (CMV) by the time they reach forty years of age. Whereas most of these CMV infections are well controlled by the immune system, congenital infection can lead to serious health effects and death for the fetus and neonate. With clear evidence that risk to the fetus is lower during chronic maternal infection, and varies in association with gestational age at the time of primary maternal infection, further research on humoral immune responses to primary CMV infection during pregnancy is needed. Here, systems serology tools were applied to characterize antibody responses to CMV infection among pregnant and non-pregnant women experiencing either primary or chronic infection. Whereas strikingly different antibody profiles were observed depending on infection status, more limited differences were associated with pregnancy status. Beyond known differences in IgM responses that are used clinically for identification of primary infection, distinctions observed in IgA and FcγR binding antibody responses and among viral antigen specificities accurately predicted infection status in a cross-sectional cohort. Leveraging machine learning, longitudinal samples were also used to define an immunological clock of CMV infection from primary to chronic states and predict time since primary infection with high accuracy. Humoral responses diverged over time in an antigen-specific manner, with IgG3 responses toward tegument decreasing over time as is typical of viral infections, while those directed to pentamer and glycoprotein B were lower during acute and greatest during chronic infection. In sum, this work provides new insights into the antibody response associated with CMV infection status in the context of pregnancy, revealing aspects of humoral immunity that have the potential to improve CMV diagnostics and to support clinical trials of interventions to reduce mother-to-fetus transmission of CMV.

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

Cited by 3 publications

References 22 publications

Relationship of maternal cytomegalovirus-specific antibody responses and viral load to vertical transmission risk following primary maternal infection in a rhesus macaque model

Relationship of maternal cytomegalovirus-specific antibody responses and viral load to vertical transmission risk following primary maternal infection in a rhesus macaque model

Relationship of maternal cytomegalovirus-specific antibody responses and viral load to vertical transmission risk following primary maternal infection in a rhesus macaque model

Discrimination of Primary and Chronic CMV Infection based on Humoral Immune Profiles in Pregnancy

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