Abstract
BackgroundViral 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.ResultsWe 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.ConclusionsTogether, 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.
Highlights
The major contribution to outcome in patients with Ebola virus disease (EVD) is viral load [1, 2]
Any perturbation in the fidelity of genome replication that increases the rate of mutation can lead to error catastrophe where synonymous and nonsynonymous changes lead to a degradation of viral protein function and a loss in viral RNA synthesis
To investigate the diversity underlying dominant viral genome sequences in patients with Ebola virus (EBOV), we examined transcriptome data from blood samples that we had either previously sequenced [1, 5, 9] or that had been sequenced for this study
Summary
The major contribution to outcome in patients with Ebola virus disease (EVD) is viral load [1, 2]. Any perturbation in the fidelity of genome replication that increases the rate of mutation can lead to error catastrophe where synonymous and nonsynonymous changes lead to a degradation of viral protein function and a loss in viral RNA synthesis. This can be exploited therapeutically where drugs such as ribavirin [12] and favipiravir [13] can be used to drive the replication of RNA viruses towards being less fit. To investigate the effects of these minor variants, blood samples from patients with acute EVD were deeply sequenced
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