Abstract
Human cytomegalovirus (HCMV) infection is the leading non-genetic cause of congenital birth defects worldwide. While several studies have addressed the genetic composition of viral populations in newborns diagnosed with HCMV, little is known regarding mother-to-child viral transmission dynamics and how therapeutic interventions may impact within-host viral populations. Here, we investigate how preexisting CMV-specific antibodies shape the maternal viral population and intrauterine virus transmission. Specifically, we characterize the genetic composition of CMV populations in a monkey model of congenital CMV infection to examine the effects of passively-infused hyperimmune globulin (HIG) on viral population genetics in both maternal and fetal compartments. In this study, 11 seronegative, pregnant monkeys were challenged with rhesus CMV (RhCMV), including a group pretreated with a standard potency HIG preparation (n = 3), a group pretreated with a high-neutralizing potency HIG preparation (n = 3), and an untreated control group (n = 5). Targeted amplicon deep sequencing of RhCMV glycoprotein B and L genes revealed that one of the three strains present in the viral inoculum (UCD52) dominated maternal and fetal viral populations. We identified minor haplotypes of this strain and characterized their dynamics. Many of the identified haplotypes were consistently detected at multiple timepoints within sampled maternal tissues, as well as across tissue compartments, indicating haplotype persistence over time and transmission between maternal compartments. However, haplotype numbers and diversity levels were not appreciably different between control, standard-potency, and high-potency pretreatment groups. We found that while the presence of maternal antibodies reduced viral load and congenital infection, it had no apparent impact on intrahost viral genetic diversity at the investigated loci. Interestingly, some minor haplotypes present in fetal and maternal-fetal interface tissues were also identified as minor haplotypes in corresponding maternal tissues, providing evidence for a loose RhCMV mother-to-fetus transmission bottleneck even in the presence of preexisting antibodies.
Highlights
Human cytomegalovirus (HCMV) is a member of the β-herpesvirus family and a ubiquitous pathogen that establishes lifelong infection in its host
Using viral DNA isolated from a monkey model of congenital CMV infection, we investigated the impact of passively-administered maternal antibodies on the genetic composition of the maternal virus population and that transmitted to the fetus
Our analysis focused on regions of two CMV genes that encode glycoproteins known to facilitate viral cellular entry and to be targeted by CMV-specific antibodies
Summary
Human cytomegalovirus (HCMV) is a member of the β-herpesvirus family and a ubiquitous pathogen that establishes lifelong infection in its host. While initial HCMV infection is typically asymptomatic in the setting of intact host immunity, congenitally infected infants, immune-compromised individuals, and transplant recipients can suffer adverse HCMV-related outcomes [2,3,4]. HCMV impacts approximately 1 in 150 live-born infants worldwide, making this virus the leading infectious cause of congenital birth defects. Among infants infected at birth, 10–20% will develop long-term sequelae including sensorineural hearing loss, microcephaly, and cognitive impairment [2]. While congenital infection could be seeded from the maternal genital tract [5,6], most cases of transmission are thought to occur transplacentally [7,8]. HCMV can be disseminated throughout the developing fetus with HCMV detectable in multiple fetal tissues in almost 50% of cases [11]
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