Mixed Infection and Strain Diversity in Congenital Cytomegalovirus Infection

Ross, Shannon A.; Novák, Zdeněk; Pati, Sunil; Patro, A. Raj Kumar; Blumenthal, Jennifer; Danthuluri, Vishwanath R.; Ahmed, Amina; Michaels, Marian G.; Sánchez, Pablo J.; Bernstein, David I.; Tolan, Robert W.; Palmer, April; Britt, William J.; Fowler, Karen B.; Boppana, Suresh B.

doi:10.1093/infdis/jir457

Cited by 77 publications

(86 citation statements)

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“…In this study, we analyzed the proportion of reinfections or mixed infections by studying the viral population divergence across time or compartments, estimating that approximately one-third of infections were mixed or reinfections. This number is similar to previous estimates based on genotype data (19) but is likely to be an underestimate because our analysis requires a change in population structure that may not occur in stable multiple strain infections. The genome-wide intrahost diversity in putative mixed infections was statistically identical to single strain infections, suggesting that infection status does not correlate with viral diversity in neonates and infants.…”

Section: Discussionsupporting

confidence: 81%

“…HCMV thus exists within hosts as a heterogeneous collection of diverse but related genomes, herein termed a population, rather than a single sequence. The high levels of intrahost genetic diversity in HCMV infections are seen across a range of human hosts, from healthy adults (14) and children (18) to congenitally infected infants (19), transplant recipients (17), and AIDS patients (20). The clinical importance of HCMV genetic diversity is still debated (21), but increasing evidence suggests a correlation with HCMV pathogenesis.…”

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confidence: 99%

“…HCMV is capable of infecting a wide range of host organs and cell types, and in vivo infection leads to widespread viral dissemination. Multiple reports show that HCMV genotypes and total levels of diversity differ between host organs, a phenomenon referred to as compartmentalization (11,19,25,26). More recently, whole genome sequencing showed that HCMV populations sampled from different compartments can be as divergent as sequences sampled from unrelated hosts (11).…”

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Limits and patterns of cytomegalovirus genomic diversity in humans

Renzette

Pokalyuk

Gibson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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112

129

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Human cytomegalovirus (HCMV) exhibits surprisingly high genomic diversity during natural infection although little is known about the limits or patterns of HCMV diversity among humans. To address this deficiency, we analyzed genomic diversity among congenitally infected infants. We show that there is an upper limit to HCMV genomic diversity in these patient samples, with ∼25% of the genome being devoid of polymorphisms. These low diversity regions were distributed across 26 loci that were preferentially located in DNA-processing genes. Furthermore, by developing, to our knowledge, the first genome-wide mutation and recombination rate maps for HCMV, we show that genomic diversity is positively correlated with these two rates. In contrast, median levels of viral genomic diversity did not vary between putatively single or mixed strain infections. We also provide evidence that HCMV populations isolated from vascular compartments of hosts from different continents are genetically similar and that polymorphisms in glycoproteins and regulatory proteins are enriched in these viral populations. This analysis provides the most highly detailed map of HCMV genomic diversity in human hosts to date and informs our understanding of the distribution of HCMV genomic diversity within human hosts.human cytomegalovirus | HCMV | congenital CMV | virology | evolution

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Section: Discussionsupporting

confidence: 81%

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confidence: 99%

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confidence: 99%

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Limits and patterns of cytomegalovirus genomic diversity in humans

Renzette

Pokalyuk

Gibson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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112

129

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“…In addition, there seem to be several strains of CMV that infect humans, so reinfection can occur. Therefore, secondary infection, may be due to reactivation or exposure to a new strain [2][3][4] . Congenital infection is the result of viral transplacental transmission.…”

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confidence: 99%

“…Fetal MRI may improve the prognostic evaluation, especially when brain abnormalities are detected or suspected by ultrasound [7] . The detection of secondary infection or reactivation with human CMV in pregnant women is a real challenge to obstetricians [4] . The current case is a secondary CMV infection resulting in mid trimester fetus with a severe cerebral epidural hemorrhage.…”

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Fetal Epidural Hemorrhage Following Non Primary CMV Infection: A Case Report

Celentano¹

2015

JGNB

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Cytomegalovirus (CMV) is a common cause of intrauterine infection, and occurs in 0.2-2.2% of all live births in western countries [1] . Primary infection is defined as CMV infection in previously seronegative woman. After the primary infection the virus becomes dormant and exists in a latent state, from which it can be reactivated. In addition, there seem to be several strains of CMV that infect humans, so reinfection can occur. Therefore, secondary infection, may be due to reactivation or exposure to a new strain [2][3][4] . Congenital infection is the result of viral transplacental transmission. Preconceptional immunity is protective against vertical transmission, with a rate of intrauterine transmission following primary infection during pregnancy of 30-40%, compared with only 1% following secondary infection [1] . Within the infected fetuses 10-15% will demonstrate symptoms at birth, and 20-30% will die [2] . Most of the infected infants have no signs or symptoms at birth, but 5 to 15% will develop sequelae due to peculiar neurotrophic behavior of human CMV2. Screening for CMV infection is based on maternal serology, while virus isolation from amniotic fluid is the mainstay for prenatal diagnosis of fetal infection [5] . Ultrasonographic findings are helpful but not diagnostic, because the features are present in other intrauterine infections and diseases [5] . Commonly observed findings consist in ventriculomegaly, microcephaly, calcifications, periventricular echogenicity and pseudocysts, intracranial hemorrhage, cortical anomalies, intraventricular synechie, cerebellar abnormalities, hepatosplenomegaly and hyperechoic bowel [6] . Fetal MRI may improve the prognostic evaluation, especially when brain abnormalities are detected or suspected by ultrasound [7] . The detection of secondary infection or reactivation with human CMV in pregnant women is a real challenge to obstetricians [4] . The current case is a secondary CMV infection resulting in mid trimester fetus with a severe cerebral epidural hemorrhage.A 30 years-old woman gravida-1 at 20 weeks gestation was referred due to suspected hydrocephaly. A detailed scan revealed a hyper-echoic space-occupying lesion overlying the left temporo-parietal region ( Figure 1A). The anterior horns of the ventricles appeared prominent, although the right lateral atria measurement in transverse section was within normal range with mild midline shift. Cavum septum pellucidi and third ventricle were unidentified. The fourth ventricle appeared dilated. Ultrasound scan revealed also a hyper-echoic bowel.MRI was performed by using Philips Achieva 1,5T (Philips Medical Systems, Netherlands) and a phased-array Sense-XLTorso coil. Fetal brain was evaluated with a single-shot turbo spin echo sequence (TSE) in the coronal, sagittal and axial planes. Gradient echo (GE) T1-weighted, GE T1-weighted with selective water excitation (WATS) and GE T2*-weighted sequences were acquired and confirmed the diagnosis of epidural hemorrhage ( Figure 1B-1C). Predisposing maternal conditions at...

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Cytomegalovirus infection in pregnancy

Davis

King

Kourtis

2017

Birth Defects Research

111

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Cytomegalovirus (CMV) is a DNA herpesvirus that is common worldwide. The two known main sources of primary CMV infection during pregnancy are through sexual activity and contact with young children. Primary infection occurs in approximately 1 to 4% of pregnancies, and is mostly asymptomatic in immunocompetent adults. However, primary infection may manifest as a mild mononucleosis or flu-like syndrome with persistent fever and fatigue. CMV can be transmitted from mother-to-child in utero, intrapartum, or during breastfeeding. Intrauterine transmission can lead to congenital CMV infection, a leading cause of permanent hearing and vision loss and neurological disability among children. Congenital CMV transmission rates are as high as 50% in women who acquire primary CMV infection during pregnancy, and less than 2% in women with nonprimary infection. There is no licensed CMV vaccine. Good hygiene practices and avoiding intimate contact with young children (e.g., kissing on the mouth and sharing utensils) have been suggested as an approach to prevent maternal primary CMV infection during pregnancy, but remains an unproven method of reducing the risk of congenital CMV infection. Approximately 1 in 10 infants who acquire CMV in utero will have clinical signs at birth, and an additional 10 to 15% will go on to develop late-onset sequelae. Antiviral treatment prenatally and postnatally has not proven effective at preventing congenital or postnatal CMV infection, and is not recommended for routine clinical care. However, antiviral treatment when initiated in the first month of life for symptomatic congenital CMV infection is recommended for improved neurodevelopmental and audiologic outcomes. Birth Defects Research 109:336-346, 2017. © 2017 Wiley Periodicals, Inc.

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Mixed Infection and Strain Diversity in Congenital Cytomegalovirus Infection

Abstract: Infection with multiple CMV strains occurs in infants with congenital CMV infection. The impact of intrauterine infection with multiple virus strains on the pathogenesis and long-term outcome remains to be elucidated.

Cited by 77 publications

References 32 publications

Limits and patterns of cytomegalovirus genomic diversity in humans

Limits and patterns of cytomegalovirus genomic diversity in humans

Fetal Epidural Hemorrhage Following Non Primary CMV Infection: A Case Report

Cytomegalovirus infection in pregnancy

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