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.
Highlights
| | | human cytomegalovirus diversity whole genome sequencing | superinfection recombination understanding intrahost Human cytomegalovirus (HCMV) evolution, in relation to HCMV compartmentalization and how this impacts on congenital and transplant [5] infections as well as for the design of effective preventative and treatment measures
Recent sequencing efforts have revealed this heterogeneity may manifest within a single patient, leading to estimates of genome-wide intrahost diversity that rival those of persistent RNA viruses, such as HIV and hepatitis C virus (HCV) [2,3,4,5,6]
On average, observed within-host HCMV diversity for set A (Fig. 1A) was higher than that of other herpesviruses [EBV, HSV, and varicella zoster virus (VZV)] (Fig. 1B) but similar to the diversity seen in 50 samples collected at a single time point from both 35 immunosuppressed children and adults and 15 congenitally infected patients (Fig. 1A)
Summary
| | | human cytomegalovirus diversity whole genome sequencing | superinfection recombination understanding intrahost HCMV evolution, in relation to HCMV compartmentalization and how this impacts on congenital and transplant [5] infections as well as for the design of effective preventative and treatment measures. We reconstruct viral strain haplotypes to pinpoint the timing of HCMV superinfections occurring within the study sampling time frame and uncover within-host viral recombination. From these results, we identify likely sources of infection and demonstrate probable selection for recombinant viruses. Distinguishing diversity that is due to superinfections and/or recombination from diversity due to de novo mutation is critical to Author contributions: R.A.G. and J.B. designed research; J.C., S.R., C.J.H., J.M.B., D.P.D., H.T., R.W., and R.A.G. performed research; P.V., A.J.J.W., A.U.T., and R.A.G. contributed new reagents/analytic tools; J.C., S.R., J.M.B., R.A.G., and J.B. analyzed data; and J.C., C.J.H., and J.B. wrote the paper
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