Deep sequencing of viral genomes provides insight into the evolution and pathogenesis of varicella zoster virus and its vaccine in humans.
Deep sequencing of viral genomes provides insight into the evolution and pathogenesis of varicella zoster virus and its vaccine in humans.
复制标题
DOI：
10.1093/molbev/mst210
复制
发表时间：
2014-02
影响因子：
10.7
通讯作者：
Breuer J
中科院分区：
文献类型：
--
作者：
Depledge DP;Kundu S;Jensen NJ;Gray ER;Jones M;Steinberg S;Gershon A;Kinchington PR;Schmid DS;Balloux F;Nichols RA;Breuer J
接种vOka疫苗可预防儿童和易感成人患水痘。vOka疫苗株包含基因型的混合物，尽管减毒，但在少数接受者中引起皮疹。像野生型病毒一样，疫苗在神经元组织中建立潜伏期，随后可以重新激活以引起带状疱疹（带状疱疹）。使用基于杂交的方法，我们直接从皮肤病变中纯化和测序vOka。我们表明，存在于疫苗中的等位基因可以从病变中恢复，并证明接种和病变形成之间存在严重的瓶颈。任何一个病变的基因型似乎都是从一个到三个疫苗基因型传下来的，新突变的频率很低。皮疹中不存在单一的vOka单倍型，也不存在新的突变，这表明新的突变或与野生型的重组对于vOka皮疹的进化都不是至关重要的。相反，由衰减产生的等位基因（即，不是来源于自由生活的病毒）在皮疹基因型中以较低的频率存在。我们确定了11个基因座，在该基因座上选择了vOka皮疹形成中的祖先等位基因，并显示从潜伏期重新激活的皮疹中的基因型不能与接种后立即发生的皮疹区分开来。我们的结论是，vOka疫苗，虽然异质性，还没有演变成形成皮疹，通过积极的选择在准种的模式，而是在疫苗生产过程中基本上是中性的等位基因已被选择对人类受试者，使我们能够确定皮疹形成的关键位点。
Immunization with the vOka vaccine prevents varicella (chickenpox) in children and susceptible adults. The vOka vaccine strain comprises a mixture of genotypes and, despite attenuation, causes rashes in small numbers of recipients. Like wild-type virus, the vaccine establishes latency in neuronal tissue and can later reactivate to cause Herpes zoster (shingles). Using hybridization-based methodologies, we have purified and sequenced vOka directly from skin lesions. We show that alleles present in the vaccine can be recovered from the lesions and demonstrate the presence of a severe bottleneck between inoculation and lesion formation. Genotypes in any one lesion appear to be descended from one to three vaccine-genotypes with a low frequency of novel mutations. No single vOka haplotype and no novel mutations are consistently present in rashes, indicating that neither new mutations nor recombination with wild type are critical to the evolution of vOka rashes. Instead, alleles arising from attenuation (i.e., not derived from free-living virus) are present at lower frequencies in rash genotypes. We identify 11 loci at which the ancestral allele is selected for in vOka rash formation and show genotypes in rashes that have reactivated from latency cannot be distinguished from rashes occurring immediately after inoculation. We conclude that the vOka vaccine, although heterogeneous, has not evolved to form rashes through positive selection in the mode of a quasispecies, but rather alleles that were essentially neutral during the vaccine production have been selected against in the human subjects, allowing us to identify key loci for rash formation.
登录
查看更多内容
影响因子：
46.9
作者：
Loman, Nicholas J.;Misra, Raju V.;Pallen, Mark J.
通讯作者：
Pallen, Mark J.
影响因子：
6.4
作者：
Banovic, Tatjana;Yanilla, Mayonelo;Nourse, Clare B.
通讯作者：
Nourse, Clare B.
影响因子：
6.4
作者：
LaRussa, P;Steinberg, S;Gershon, A
通讯作者：
Gershon, A
影响因子：
6.4
作者：
Levy, O;Orange, JS;Exley, M
通讯作者：
Exley, M
影响因子：
12.7
作者：
Chen, Jason J.;Gershon, Anne A.;Gershon, Michael D.
通讯作者：
Gershon, Michael D.