Human cytomegalovirus haplotype reconstruction reveals high diversity due to superinfection and evidence of within-host recombination.
Houldcroft, Charlotte J
Bryant, Josephine M
Depledge, Daniel P
Worth, Austen JJ
Tamuri, Asif U
Proc Natl Acad Sci U S A
Proceedings of the National Academy of Sciences
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Cudini, J., Roy, S., Houldcroft, C. J., Bryant, J. M., 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.. Proc Natl Acad Sci U S A, 116 (12), 5693-5698. https://doi.org/10.1073/pnas.1818130116
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.
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
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.
External DOI: https://doi.org/10.1073/pnas.1818130116
This record's URL: https://www.repository.cam.ac.uk/handle/1810/289897