Whole-Genome Approach to Assessing Human Cytomegalovirus Dynamics in Transplant Patients Undergoing Antiviral Therapy

Suárez, Nicolás M.; Blyth, Emily; Li, Kathy; Ganzenmueller, Tina; Camiolo, Salvatore; Avdic, Selmir; Withers, Barbara; Linnenweber-Held, Silvia; Gwinner, Wilfried; Dhingra, Akshay; Heim, Albert; Schulz, Thomas F.; Gunson, Rory; Gottlieb, David; Slobedman, Barry; Davison, Andrew J.

doi:10.3389/fcimb.2020.00267

Cited by 18 publications

(19 citation statements)

References 40 publications

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“…Our estimates of the much lower level of intrahost diversity in single-strain reactivations in comparison with multiple-strain reactivations also corroborates the findings of previous studies in the blood compartment of immunocompromised patients (Cudini et al, 2019). This underlines the importance of controlling for the presence of multiple strains in studies of HCMV diversity in clinical specimens (Houldcroft et al, 2020;Suaŕez et al, 2020). Low levels of intrahost diversity in single-strain infections and reactivations stem from a small number of variants usually present at low frequency (Figure S4), a situation that makes diversity estimates very susceptible to outliers (Figure S2) (Suaŕez et al, 2019b).…”

Section: Discussionsupporting

confidence: 90%

Human Cytomegalovirus Genome Diversity in Longitudinally Collected Breast Milk Samples

Götting

Lazar²,

Suárez

et al. 2021

Front. Cell. Infect. Microbiol.

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Reactivation and shedding of human cytomegalovirus (HCMV) in breast milk during lactation is highly frequent in HCMV-seropositive mothers. This represents a key transmission route for postnatal HCMV infection and can lead to severe disease in preterm neonates. Little is known about HCMV strain composition or longitudinal intrahost viral population dynamics in breast milk from immunocompetent women. We performed HCMV-specific target enrichment and high-throughput sequencing of 38 breast milk samples obtained in Germany between days 10 and 60 postpartum from 15 mothers with HCMV DNA lactia, and assembled HCMV consensus sequences de novo. The genotype distribution and number of HCMV strains present in each sample were determined by quantifying genotype-specific sequence motifs in 12 hypervariable viral genes, revealing a wide range of genotypes (82/109) for these genes in the cohort and a unique, longitudinally stable strain composition in each mother. Reactivation of up to three distinct HCMV strains was detected in 8/15 of mothers, indicating that a representative subset of the woman’s HCMV reservoir might be locally reactivated early during lactation. As described previously, nucleotide diversity of samples with multiple strains was much higher than that of samples with single strains. Breast milk as a main source of postnatal mother-to-infant transmission may serve as a repository for viral diversity and thus play an essential role in the natural epidemiology of HCMV.

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Section: Discussionsupporting

confidence: 90%

Human Cytomegalovirus Genome Diversity in Longitudinally Collected Breast Milk Samples

Götting

Lazar²,

Suárez

et al. 2021

Front. Cell. Infect. Microbiol.

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“…In addition to mutations selected in vitro (such as the UL/b′ example), variation occurs naturally in vivo. Whole-genome sequencing of clinical samples is starting to describe the level of variation in terms of genotypes of numbered genes and document that not all circulating strains encode exactly the same repertoire of genes [146][147][148] . The extensive variation seen has the potential to affect virus pathogenesis in vivo, but no definitive studies have yet been reported.…”

Section: Box 1 | Human Cytomegalovirus Strains and Their Genomesmentioning

confidence: 99%

Pathogenesis of human cytomegalovirus in the immunocompromised host

2021

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“…These variable loci result in a limited number of distinct genotypes that have been extensively used to study population-level HCMV diversity found within and between hosts, primarily focusing on glycoproteins such as gB, gN, gO and gH (Wang et al, 2021). Various techniques, including restriction fragment length polymorphism (RLFP) analysis (Huang et al, 1980), targeted amplicon sequencing (Puchhammer-Stöckl et al, 2006) (Coaquette et al, 2004) (Sowmya & Madhavan, 2009) (Hasing et al, 2021), and whole-genome sequencing (Dhingra et al, 2021) (Suárez et al, 2020) have been used. With increasing sequencing depth of next-generation sequencing platforms, the detection of low-frequency variants, i.e.…”

Section: Introductionmentioning

confidence: 99%

“…minors became possible (Görzer et al, 2010). Currently, there is mounting evidence that HCMV exists as a heterogeneous collection of genomes with variations in composition and distribution between anatomical compartments (Renzette et al, 2013)(Hage et al, 2017) and over time (Dhingra et al, 2021)(Suárez et al, 2020)(Görzer et al, 2010)(Hage et al, 2017). However, in samples with mixed strains, determination of individual consensus sequences using short reads presents a challenge.…”

Section: Introductionmentioning

confidence: 99%

Human cytomegalovirus strain diversity and dynamics reveal the donor lung as a major contributor after transplantation

Külekci

Schwarz

Brait

et al. 2022

Preprint

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Mixed human cytomegalovirus (HCMV) strain infections are frequent in lung transplant recipients (LTRs). To date, the influence of the donor (D) and recipient (R) HCMV-serostatus on intra-host HCMV strain composition and replication dynamics after transplantation is only poorly understood.Here, we investigated ten pre-transplant lungs from HCMV-seropositive donors, and 163 sequential HCMV-DNA positive plasma and bronchoalveolar lavage samples from 50 LTRs with multiviremic episodes post-transplantation. The study cohort included D+R+ (38%), D+R− (36%), and D−R+ (26%) patients. All samples were subjected to quantitative genotyping by short amplicon deep sequencing, and 24 thereof were additionally PacBio long-read sequenced for genotype linkages.We find that D+R+ patients show a significantly elevated intra-host strain diversity compared to D+R− and D−R+ patients (P=0.0089). Both D+ patient groups display significantly higher replication dynamics than D− patients (P=0.0061). Five out of ten pre-transplant donor lungs were HCMV-DNA positive, whereof in three multiple HCMV strains were detected, indicating that multi-strain transmission via lung transplantation is likely. Using long reads, we show that intra-host haplotypes can share distinctly linked genotypes, which limits overall intra-host diversity in mixed infections. Together, our findings demonstrate donor-derived strains as a main source for increased HCMV strain diversity and dynamics post-transplantation, while a relatively limited number of intra-host strains may facilitate rapid adaptation to changing environments in the host. These results foster targeted strategies to mitigate the potential transmission of the donor strain reservoir with the allograft.

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Whole-Genome Approach to Assessing Human Cytomegalovirus Dynamics in Transplant Patients Undergoing Antiviral Therapy

Cited by 18 publications

References 40 publications

Human Cytomegalovirus Genome Diversity in Longitudinally Collected Breast Milk Samples

Human Cytomegalovirus Genome Diversity in Longitudinally Collected Breast Milk Samples

Pathogenesis of human cytomegalovirus in the immunocompromised host

Human cytomegalovirus strain diversity and dynamics reveal the donor lung as a major contributor after transplantation

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