Mixed cytomegalovirus genotypes in HIV positive mothers show compartmentalization and distinct patterns of transmission to infants
Abstract
Cytomegalovirus (CMV) is the commonest cause of congenital infection (cCMVi) and particularly so among infants born to HIV-infected women. Studies of 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.
Data availability
Sequence reads have been deposited in NCBI Sequence Read Archive under BioProject ID PRJNA605798.
Article and author information
Author details
Funding
EUFP7 (304875)
- Judith Breuer
UCL/UCLH NIHR Biomedical Research Centre
- Judith Breuer
Sir Henry Wellcome Fellowship
- Sofia Morfopoulou
Sir Henry Wellcome Fellowships
- Josephine Bryant
Wellcome Trust (204870)
- Paul Griffiths
NIH National Institute of Allergy and Infectious Diseases (AI087369)
- Jennifer A Slyker
NIH National Institute of Allergy and Infectious Diseases (AI027757)
- Jennifer A Slyker
NIH National Institute of Allergy and Infectious Diseases (AI076105)
- Carey Farquhar
NIH National Institute of Allergy and Infectious Diseases (AI087399)
- Carey Farquhar
National Institute of Child Health and Human Development (HD057773-01)
- Carey Farquhar
National Institute of Child Health and Human Development (HD054314)
- Carey Farquhar
Rosetreees Trust PhD Studentship (M876)
- Juanita Pang
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Margaret Stanley, University of Cambridge, United Kingdom
Version history
- Received: September 17, 2020
- Accepted: December 31, 2020
- Accepted Manuscript published: December 31, 2020 (version 1)
- Version of Record published: January 13, 2021 (version 2)
Copyright
© 2020, Pang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,042
- views
-
- 151
- downloads
-
- 17
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Cell Biology
- Genetics and Genomics
Recurrent joint bleeding in hemophilia patients frequently causes hemophilic arthropathy (HA). Drastic degradation of cartilage is a major characteristic of HA, but its pathological mechanisms has not yet been clarified. In HA cartilages, we found server matrix degradation and increased expression of DNA methyltransferase proteins. We thus performed genome-wide DNA methylation analysis on human HA (N=5) and osteoarthritis (OA) (N=5) articular cartilages, and identified 1228 differentially methylated regions (DMRs) associated with HA. Functional enrichment analyses revealed the association between DMR genes (DMGs) and extracellular matrix (ECM) organization. Among these DMGs, Tenascin XB (TNXB) expression was down-regulated in human and mouse HA cartilages. The loss of Tnxb in F8-/- mouse cartilage provided a disease-promoting role in HA by augmenting cartilage degeneration and subchondral bone loss. Tnxb knockdown also promoted chondrocyte apoptosis and inhibited phosphorylation of AKT. Importantly, AKT agonist showed chondroprotective effects following Tnxb knockdown. Together, our findings indicate that exposure of cartilage to blood leads to alterations in DNA methylation, which is functionally related to ECM homeostasis, and further demonstrate a critical role of TNXB in HA cartilage degeneration by activating AKT signaling. These mechanistic insights allow development of potentially new strategies for HA cartilage protection.
-
- Developmental Biology
- Genetics and Genomics
Germline epigenetic programming, including genomic imprinting, substantially influences offspring development. Polycomb Repressive Complex 2 (PRC2) plays an important role in Histone 3 Lysine 27 trimethylation (H3K27me3)-dependent imprinting, loss of which leads to growth and developmental changes in mouse offspring. In this study, we show that offspring from mouse oocytes lacking the PRC2 protein Embryonic Ectoderm Development (EED) were initially developmentally delayed, characterised by low blastocyst cell counts and substantial growth delay in mid-gestation embryos. This initial developmental delay was resolved as offspring underwent accelerated fetal development and growth in late gestation resulting in offspring that were similar stage and weight to controls at birth. The accelerated development and growth in offspring from Eed-null oocytes was associated with remodelling of the placenta, which involved an increase in fetal and maternal tissue size, conspicuous expansion of the glycogen-enriched cell population, and delayed parturition. Despite placental remodelling and accelerated offspring fetal growth and development, placental efficiency, and fetal blood glucose levels were low, and the fetal blood metabolome was unchanged. Moreover, while expression of the H3K27me3-imprinted gene and amino acid transporter Slc38a4 was increased, fetal blood levels of individual amino acids were similar to controls, indicating that placental amino acid transport was not enhanced. Genome-wide analyses identified extensive transcriptional dysregulation and DNA methylation changes in affected placentas, including a range of imprinted and non-imprinted genes. Together, while deletion of Eed in growing oocytes resulted in fetal growth and developmental delay and placental hyperplasia, our data indicate a remarkable capacity for offspring fetal growth to be normalised despite inefficient placental function and the loss of H3K27me3-dependent genomic imprinting.