Defining the Timing of Cytomegalovirus Acquisition in Infants with Prenatal Zika Virus Exposure: Insights into Fetal Immune Modulation
Finn Eckes, Anika Shah, Elaina Razo, Nick Krabbe, Jennifer Hayes, Emma MohrAbstract
Background
This study investigates the timing of Cytomegalovirus (CMV) acquisition in rhesus macaque infants, specifically exploring whether prenatal exposure to Zika virus (ZIKV) alters the fetal immune system and influences functional immune responses, like the timing of CMV acquisition during childhood. CMV is a ubiquitous virus in human and macaque populations with nearly 100% seroprevalence by adulthood, with most individuals acquiring CMV in early childhood. Previous research indicates that exposure to other maternal infections, such as HIV, leads to earlier acquisition of CMV infection in childhood, even when HIV is not vertically transmitted. We hypothesized that prenatal exposure to ZIKV might have a similar effect.
Methods
Dams in the ZIKV cohort were inoculated with ZIKV during the first trimester. Mothers and their infants were co-housed during the first year of infant life. Infants were subsequently peer-housed until 2 years of age. All infants were followed for 2 years after delivery. 174 banked blood samples from ZIKV-exposed and control infant macaques at 12, 18, and 24 months were tested. Samples firstly underwent commercial rhesus CMV (rhCMV) Polymerase Chain Reaction (PCR) analysis. PCR result analysis identified a need for CMV antibody testing, leading to the retrieval of 32 24-month time point infant samples from the prior cohort. To assess if maternal CMV serology presented at the time of infant delivery, dam samples corresponding to CMV antibody-tested infants were additionally identified. 32 corresponding dam samples were retrieved for analysis of maternal CMV serology at the time of delivery. CMV antibody tests were additionally conducted on infant samples from 12- and 18-month time points, thereby establishing a detailed serological timeline from 12, 18, and 24 months of infant age. Our final sample size was 32 infants and 23 dams.
Results
We found a similar acquisition timing of CMV IgG antibodies across ZIKV-exposed and control infants, with ~20% presenting CMV IgG at 12 months, 60% at 18 months, and 100% at 24 months in both groups. rhCMV PCR analysis CMV viremia was identified in 1 ZIKV infant at 6 months, and in 2 control infants, one at 12 months and one at 3 months. Serological testing on the positive ZIKV 6-month sample revealed CMV IgG present at 12 months, 18 months, and 24 months. All dams had rhCMV IgG detected at delivery.
Conclusions
Our findings suggest that prenatal ZIKV exposure does not alter the timing of CMV acquisition and that prenatal ZIKV exposure may not significantly alter the development of the functional immune response. We confirmed that rhCMV is a ubiquitous virus within colonies and that 20% of CMV acquisition occurs because of mother-to-infant transmission when the dams and infants were co-housed.