Human cytomegalovirus haplotype reconstruction reveals high diversity due to superinfection and evidence of within-host recombination
Human cytomegalovirus haplotype reconstruction reveals high diversity due to superinfection and evidence of within-host recombination
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DOI：
10.1073/pnas.1818130116
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发表时间：
2019-03-19
影响因子：
11.1
通讯作者：
Breuer, Judith
中科院分区：
文献类型：
--
作者：
Cudini, Juliana;Roy, Sunando;Breuer, Judith
最近的测序工作导致对人类巨细胞病毒（HCMV）全基因组宿主内多样性的估计，可与持久性RNA病毒的多样性相媲美[Renzette N，Bhattacharjee B，詹森JD，吉布森L，Kowalik TF（2011）PLoS Pathog 7：e1001344]。在这里，我们对从免疫功能低下儿童的单个和纵向收集的血液样本中回收的HCMV基因组进行深度测序，以表明宿主内高HCMV核苷酸多样性的观察结果可以通过遗传上遥远的菌株引起的混合感染的频繁发生来解释。为了证实这一发现，我们从短读段序列数据重建了宿主内病毒单倍型。我们证实，在未混合感染的宿主内HCMV核苷酸多样性是不大于其他DNA病毒分析相同的测序和生物信息学方法，大大低于人类免疫缺陷病毒和丙型肝炎病毒。通过解析患者体内的单个病毒单倍型，我们重建了重复感染菌株的时间、可能的起源和自然史。我们发现了遗传上不同的HCMV毒株之间宿主内重组的证据，观察到含有非重组片段的亲本病毒的丢失。这些数据表明选择含有重组片段的菌株，产生关于HCMV进化和发病机制的可检验的假设。这些结果强调了一些样品中存在的高HCMV多样性是由多种不同毒株的共感染引起的，并保证了单株HCMV感染的宿主多样性不大于其他疱疹病毒。
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.