Human cytomegalovirus haplotype reconstruction reveals high diversity due to superinfection and evidence of within-host recombination.
View / Open Files
Authors
Roy, Sunando
Tallis, Dr Josephine Bryant
Tutill, Helena
Veys, Paul
Worth, Austen JJ
Tamuri, Asif U
Publication Date
2019-03Journal Title
Proceedings of the National Academy of Sciences of the United States of America
ISSN
0027-8424
Publisher
National Academy of Sciences
Volume
116
Issue
12
Pages
5693-5698
Language
eng
Type
Article
This Version
AM
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Cudini, J., Roy, S., Houldcroft, C., Tallis, D. J. B., Depledge, D. P., Tutill, H., Veys, P., et al. (2019). Human cytomegalovirus haplotype reconstruction reveals high diversity due to superinfection and evidence of within-host recombination.. Proceedings of the National Academy of Sciences of the United States of America, 116 (12), 5693-5698. https://doi.org/10.1073/pnas.1818130116
Abstract
Recent sequencing efforts have led to estimates of human cytomegalovirus
(HCMV) genome-wide intrahost diversity that rival those of
persistent RNA viruses [Renzette N, Bhattacharjee B, Jensen JD,
Gibson L, Kowalik TF (2011) PLoS Pathog 7:e1001344]. Here, we deep
sequence HCMV genomes recovered from single and longitudinally
collected blood samples from immunocompromised children to show
that the observations of high within-host HCMV nucleotide diversity
are explained by the frequent occurrence of mixed infections caused
by genetically distant strains. To confirm this finding, we reconstructed
within-host viral haplotypes from short-read sequence data.
We verify that within-host HCMV nucleotide diversity in unmixed
infections is no greater than that of other DNA viruses analyzed by
the same sequencing and bioinformatic methods and considerably
less than that of human immunodeficiency and hepatitis C viruses. By
resolving individual viral haplotypes within patients, we reconstruct
the timing, likely origins, and natural history of superinfecting
strains. We uncover evidence for within-host recombination between
genetically distinct HCMV strains, observing the loss of the parental
virus containing the nonrecombinant fragment. The data suggest
selection for strains containing the recombinant fragment, generating
testable hypotheses about HCMV evolution and pathogenesis.
These results highlight that high HCMV diversity present in some
samples is caused by coinfection with multiple distinct strains and
provide reassurance that within the host diversity for single-strain
HCMV infections is no greater than for other herpesviruses.
Keywords
Humans, Cytomegalovirus, Superinfection, Cytomegalovirus Infections, DNA, Viral, Sequence Analysis, DNA, Immunocompromised Host, Recombination, Genetic, Base Sequence, Haplotypes, Genome, Viral, Genome, Human, Child, Child, Preschool, Infant, Infant, Newborn, Female, Male, Genetic Variation, High-Throughput Nucleotide Sequencing
Sponsorship
D.P.D. was supported by a grant from the Medical
Research Foundation. C.J.H. was supported by Action Medical Research Grant GN2424. The PATHSEEK consortium was funded by the European Union’s Seventh Programme for research, technological development, and demonstration under grant agreement 304875.
Identifiers
External DOI: https://doi.org/10.1073/pnas.1818130116
This record's URL: https://www.repository.cam.ac.uk/handle/1810/289897
Rights
Licence:
http://www.rioxx.net/licenses/all-rights-reserved