Abstract
BackgroundThe second human pegivirus (HPgV-2) and hepatitis C virus (HCV) belong to the Flaviviridae family and share some common genome features. However, the two viruses exhibit significantly different genetic diversity. The comparison of intrahost dynamics of HPgV-2 and HCV that mainly reflect virus-host interactions is needed to elucidate their intrahost difference of genetic diversity and the possible mechanisms.MethodsIntrahost single nucleotide variations (iSNVs) were identified by means of next-generation sequencing from both cross-sectional and longitudinal samples from HPgV-2- and HCV-coinfected patients. The levels of human cytokines were quantified in the patient before and after HCV elimination by the treatment of direct-acting antivirals (DAA).ResultsUnlike HCV, the viral sequences of HPgV-2 are highly conserved among HPgV-2-infected patients. However, iSNV analysis confirmed the intrahost variation or quasispecies of HPgV-2. Almost all iSNVs of HPgV-2 did not accumulate or transmit within host over time, which may explain the highly conserved HPgV-2 consensus sequence. Intrahost variation of HPgV-2 mainly causes nucleotide transition in particular at the 3rd codon position and synonymous substitutions, indicating purifying or negative selection posed by host immune system. Cytokine data further indicate that HPgV-2 infection alone may not efficiently stimulate innate immune responses since proinflammatory cytokine expression dramatically decreased with elimination of HCV.ConclusionThis study provided new insights into the intrahost genomic variations and evolutionary dynamics of HPgV-2 as well as the impact of host immune selection and virus polymerase on virus evolution. The different genetic diversity of HPgV-2 and HCV makes HPgV-2 a potential new model to investigate RNA virus diversity and the mechanism of viral polymerase in modulating virus replication.
Highlights
The second human pegivirus (HPgV-2), a single-stranded positive-sense RNA virus was first reported in 2015 and belongs to the family of Flaviviridae (Berg et al, 2015; Kapoor et al, 2015)
We first analyzed the number of intrahost single nucleotide variations (iSNVs) and normalized them by the genome length as #iSNV/kb to represent the rate of intrahost viral diversity
The number of iSNVs is quite different among HPgV-2-infected subjects and ranges from 18.0 to 237.0 with a mean of 124.8 ± 85.2 whereas the #iSNV/kb ranges from 1.9 to 24.9 with an average of 13.2 ± 9.0 (Table 1 and Supplementary Table 5)
Summary
The second human pegivirus (HPgV-2), a single-stranded positive-sense RNA virus was first reported in 2015 and belongs to the family of Flaviviridae (Berg et al, 2015; Kapoor et al, 2015). The overall nucleotide identity among HPgV-2 consensus sequences worldwide is about 94%, and no apparent hypervariable regions are observed within HPgV-2 genome (Berg et al, 2015; Wang et al, 2018b; Rodgers et al, 2019; Sridhar et al, 2019; Forberg et al, 2020). These results indicate the significant difference of HPgV-2 and HCV with respect to their interhost genetic diversity. The comparison of intrahost dynamics of HPgV-2 and HCV that mainly reflect virus-host interactions is needed to elucidate their intrahost difference of genetic diversity and the possible mechanisms
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