Background Viral load is a major contributor to outcome in patients with Ebola virus disease (EVD), with high values leading to a fatal outcome. Evidence from the 2013–2016 Ebola virus (EBOV) outbreak indicated that different genotypes of the virus can have different phenotypes in patients. Additionally, due to the error-prone nature of viral RNA synthesis in an individual patient, the EBOV genome exists around a dominant viral genome sequence. The minor variants within a patient may contribute to the overall phenotype in terms of viral protein function. To investigate the effects of these minor variants, blood samples from patients with acute EVD were deeply sequenced. Results We examine the minor variant frequency between patients with acute EVD who survived infection with those who died. Non-synonymous differences in viral proteins were identified that have implications for viral protein function. The greatest frequency of substitution was identified at three codon sites in the L gene—which encodes the viral RNA-dependent RNA polymerase (RdRp). Recapitulating this in an assay for virus replication, these substitutions result in aberrant viral RNA synthesis and correlate with patient outcome. Conclusions Together, these findings support the notion that in patients who survived EVD, in some cases, the genetic variability of the virus resulted in deleterious mutations that affected viral protein function, leading to reduced viral load. Such mutations may also lead to persistent strains of the virus and be associated with recrudescent infections.

中文翻译：

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主要病毒基因组序列的变异有助于埃博拉病毒病患者的病毒载量和结果


背景 病毒载量是埃博拉病毒病 (EVD) 患者预后的一个主要因素，高值会导致致命的结果。 2013-2016年埃博拉病毒（EBOV）爆发的证据表明，不同基因型的病毒在患者中可能有不同的表型。此外，由于个体患者的病毒 RNA 合成容易出错，因此 EBOV 基因组存在于主要病毒基因组序列周围。患者体内的微小变异可能会影响病毒蛋白功能的整体表型。为了研究这些微小变异的影响，对急性埃博拉病毒病患者的血液样本进行了深度测序。结果我们检查了感染后幸存的急性埃博拉病毒病患者与死亡患者之间的微小变异频率。病毒蛋白中的非同义差异被发现对病毒蛋白功能有影响。最大频率的取代在 L 基因的三个密码子位点被发现，该基因编码病毒 RNA 依赖性 RNA 聚合酶 (RdRp)。在病毒复制测定中重述这一点，这些替换会导致病毒 RNA 合成异常，并与患者的治疗结果相关。结论 总之，这些发现支持这样的观点，即在埃博拉病毒病幸存者中，在某些情况下，病毒的遗传变异导致有害突变，影响病毒蛋白功能，导致病毒载量减少。此类突变还可能导致病毒株持续存在，并与复发性感染相关。