Abstract
Hepatitis C virus (HCV) and human pegivirus (HPgV), formerly GBV-C, are the only known human viruses in the Hepacivirus and Pegivirus genera, respectively, of the family Flaviviridae. We present the discovery of a second pegivirus, provisionally designated human pegivirus 2 (HPgV-2), by next-generation sequencing of plasma from an HCV-infected patient with multiple bloodborne exposures who died from sepsis of unknown etiology. HPgV-2 is highly divergent, situated on a deep phylogenetic branch in a clade that includes rodent and bat pegiviruses, with which it shares <32% amino acid identity. Molecular and serological tools were developed and validated for high-throughput screening of plasma samples, and a panel of 3 independent serological markers strongly correlated antibody responses with viral RNA positivity (99.9% negative predictive value). Discovery of 11 additional RNA-positive samples from a total of 2440 screened (0.45%) revealed 93–94% nucleotide identity between HPgV-2 strains. All 12 HPgV-2 RNA-positive cases were identified in individuals also testing positive for HCV RNA (12 of 983; 1.22%), including 2 samples co-infected with HIV, but HPgV-2 RNA was not detected in non-HCV-infected individuals (p<0.0001), including those singly infected by HIV (p = 0.0075) or HBV (p = 0.0077), nor in volunteer blood donors (p = 0.0082). Nine of the 12 (75%) HPgV-2 RNA positive samples were reactive for antibodies to viral serologic markers, whereas only 28 of 2,429 (1.15%) HPgV-2 RNA negative samples were seropositive. Longitudinal sampling in two individuals revealed that active HPgV-2 infection can persist in blood for at least 7 weeks, despite the presence of virus-specific antibodies. One individual harboring both HPgV-2 and HCV RNA was found to be seronegative for both viruses, suggesting a high likelihood of simultaneous acquisition of HCV and HPgV-2 infection from an acute co-transmission event. Taken together, our results indicate that HPgV-2 is a novel bloodborne infectious virus of humans and likely transmitted via the parenteral route.
Highlights
The only members of the Hepacivirus and Pegivirus genera that are known to infect humans are Hepatitis C virus (HCV) and human pegivirus (HPgV, formerly GB virus C/GBV-C)
Using unbiased metagenomic next-generation sequencing, we discovered and assembled the genome of a novel pegivirus from plasma corresponding to an HCV-infected patient who died from unknown sepsis
Metagenomic next-generation sequencing (NGS) and sequencebased ultra-rapid pathogen identification (SURPI) analysis done at University of California, San Francisco identified 3 reads in a plasma sample from one patient that were assembled into two contiguous sequences sharing 60% amino acid identity to simian pegivirus A (SPgV-A/GBV-A) (Fig 1A)
Summary
The only members of the Hepacivirus and Pegivirus genera that are known to infect humans are Hepatitis C virus (HCV) and human pegivirus (HPgV, formerly GB virus C/GBV-C). Novel animal hepaciviruses and pegiviruses have previously been found in multiple animal reservoirs, including bats, rodents, cows, and horses [7,8,9,10,11,12,13] While hepaciviruses such as HCV in humans and GBV-B are established hepatitis agents [14], traditional criteria for classification of viruses as pegiviruses have included phylogenetic relatedness, persistent infection in the host and, importantly, apparent lack of pathogenicity [15,16]. The reported discovery of Theiler’s disease-associated virus (EPgV-TDAV) [7], a novel pegivirus associated with acute hepatitis outbreaks in horses, belies this general classification and suggests that at least one member of the Pegivirus genus is able to cause hepatitis in its animal host
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