Mixed cytomegalovirus genotypes in HIV-positive mothers show compartmentalization and distinct patterns of transmission to infants.

Juanita Pang,Carey Farquhar,Helena Tutil,Sunando Roy,Judith Breuer,Jennifer A Slyker,Sofia Morfopoulou,James Kiarie,Alison C Roxby,Josephine Bryant,Richard A Goldstein,Soren Gantt,Rachel Williams,Juliana Cudini,Claire Atkinson,Paul Griffiths

doi:10.7554/elife.63199

Juanita Pang, Carey Farquhar + Show 14 more

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https://doi.org/10.7554/elife.63199

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Abstract

Cytomegalovirus (CMV) is the commonest cause of congenital infection and particularly so among infants born to HIV-infected women. Studies of congenital CMV infection (cCMVi) pathogenesis are complicated by the presence of multiple infecting maternal CMV strains, especially in HIV-positive women, and the large, recombinant CMV genome. Using newly developed tools to reconstruct CMV haplotypes, we demonstrate anatomic CMV compartmentalization in five HIV-infected mothers and identify the possibility of congenitally transmitted genotypes in three of their infants. A single CMV strain was transmitted in each congenitally infected case, and all were closely related to those that predominate in the cognate maternal cervix. Compared to non-transmitted strains, these congenitally transmitted CMV strains showed statistically significant similarities in 19 genes associated with tissue tropism and immunomodulation. In all infants, incident superinfections with distinct strains from breast milk were captured during follow-up. The results represent potentially important new insights into the virologic determinants of early CMV infection.

Highlights

Human cytomegalovirus (CMV) is the commonest infectious cause of congenitally acquired disability (Morton and Nance, 2006)
Between 0.2% and 2% of all live births have congenital CMV infection, and of these, an estimated 15–20% develop permanent sequelae ranging from sensorineural hearing loss to severe neurocognitive impairment (Boppana et al, 2013; Dollard et al, 2007)
While breast milk samples had greater than 70% coverage at depths of 10Â or more, the cervical and infant samples were generally of lower depth, likely due to degradation of DNA due to the age and handling of the samples; genome coverage and mean de-duplicated read depth were directly related to actual CMV genome copy number present in the input material (Figure 1—figure supplement 1)

Summary

Introduction

Human cytomegalovirus (CMV) is the commonest infectious cause of congenitally acquired disability (Morton and Nance, 2006). Between 0.2% and 2% of all live births have congenital CMV infection (cCMVi), and of these, an estimated 15–20% develop permanent sequelae ranging from sensorineural hearing loss to severe neurocognitive impairment (Boppana et al, 2013; Dollard et al, 2007). Genetics and Genomics Microbiology and Infectious Disease higher CMV viral loads in plasma, saliva, cervix, and breast milk, and a greater risk of both congenital and postnatal CMV transmission (Gantt et al, 2016a; Gantt et al, 2016b; Slyker et al, 2017; Richardson et al, 2016). Numerous studies have highlighted the negative health impacts of CMV on both HIV-infected and HIV-exposed uninfected (HEU) infants and children (Garcia-Knight et al, 2017; Gompels et al, 2012; Hsiao et al, 2013)

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