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The First Nonmammalian Pegivirus Demonstrates Efficient In Vitro Replication and High Lymphotropism.

ABSTRACT: Members of the Pegivirus genus, family Flaviviridae, widely infect humans and other mammals, including nonhuman primates, bats, horses, pigs, and rodents, but are not associated with disease. Here, we report a new, genetically distinct pegivirus in goose (Anser cygnoides), the first identified in a nonmammalian host species. Goose pegivirus (GPgV) can be propagated in goslings, embryonated goose eggs, and primary goose embryo fibroblasts, and is thus the first pegivirus that can be efficiently cultured in vitro Experimental infection of GPgV in goslings via intravenous injection revealed robust replication and high lymphotropism. Analysis of the tissue tropism of GPgV revealed that the spleen and thymus were the organs bearing the highest viral loads. Importantly, GPgV could promote clinical manifestations of goose parvovirus infection, including reduced weight gain and 7% mortality. This finding contrasts with the lack of pathogenicity that is characteristic of previously reported pegiviruses.IMPORTANCE Members of the Pegivirus genus, family Flaviviridae, widely infect humans and other mammals, but are described as causing persistent infection and lacking pathogenicity. The efficiency of in vitro replication systems for pegivirus is poor, thus limiting investigation into viral replication steps. Because of that, the pathogenesis, cellular tropism, route of transmission, biology, and epidemiology of pegiviruses remain largely uncovered. Here, we report a phylogenetically distinct goose pegivirus (GPgV) that should be classified as a new species. GPgV proliferated in cell culture in a species- and cell-type-specific manner. Animal experiments show GPgV lymphotropism and promote goose parvovirus clinical manifestations. This study provides the first cell culture model for pegivirus, opening new possibilities for studies of pegivirus molecular biology. More importantly, our findings stand in contrast to the lack of identified pathogenicity of previously reported pegiviruses, which sheds lights on the pathobiology of pegivirus.

SUBMITTER: Wu Z

PROVIDER: S-EPMC7527067 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionHuman pegivirus-1 (HPgV-1) is a so-called commensal virus for which no known associated organ disease has been found to date. Yet, it affects immune-reconstitution as previously studied in the HIV population, in whom active co-infection with HPgV-1 can modulate T and NK cell activation and differentiation leading to a protective effect against the evolution of the disease. Little is known on the effect of HPgV-1 on immune-reconstitution in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients, a patient population in which we and others have previously reported high prevalence of HPgV-1 replication. The aim of this study was to compare the immune reconstitution after allo-HSCT among HPgV-1-viremic and HPgV-1-non-viremic patients.MethodsWithin a cohort study of 40 allo-HSCT patients, 20 allo-HSCT recipients positive in plasma sample for HPgV-1 by rRT-PCR during the first year (1, 3, 6, 12 months) after transplantation were matched with 20 allo-HSCT recipients negative for HPgV-1. T and NK cell reconstitution was monitored by flow cytometry in peripheral blood samples from allo-HSCT recipients at the same time points.ResultsWe observed no significant difference in the absolute number and subsets proportions of CD4 and CD8 T cells between patient groups at any analysed timepoint. We observed a significantly higher absolute number of NK cells at 3 months among HPgV-1-viremic patients. Immunophenotypic analysis showed a significantly higher proportion of CD56bright NK cells mirrored by a reduced percentage of CD56dim NK cells in HPgV-1-positive patients during the first 6 months after allo-HSCT. At 6 months post-allo-HSCT, NK cell phenotype significantly differed depending on HPgV-1, HPgV-1-viremic patients displaying NK cells with lower CD16 and CD57 expression compared with HPgV-1-negative patients. In accordance with their less differentiated phenotype, we detected a significantly reduced expression of granzyme B in NK cells in HPgV-1-viremic patients at 6 months.DiscussionOur study shows that HPgV-1-viremic allo-HSCT recipients displayed an impaired NK cell, but not T cell, immune-reconstitution compared with HPgV-1-non-viremic patients, revealing for the first time a potential association between replication of the non-pathogenic HPgV-1 virus and immunomodulation after allo-HSCT.

Project description:The virus-encoded RNA-dependent RNA polymerase (RdRp) is responsible for viral replication, and its fidelity is closely related to viral diversity, pathogenesis, virulence, and fitness. Hepatitis C virus (HCV) and the second human pegivirus (HPgV-2) belong to the family Flaviviridae and share some features, including similar viral genome structure. Unlike HCV, HPgV-2 preserves a highly conserved genome sequence and low intrahost variation. However, the underlying mechanism remains to be elucidated. In this study, we evaluated the fidelity of HPgV-2 and HCV RdRp in an in vitro RNA polymerase reaction system. The results showed higher fidelity of HPgV-2 RdRp than HCV NS5B with respect to the misincorporation rate due to their difference in recognizing nucleoside triphosphate (NTP) substrates. Furthermore, HPgV-2 RdRp showed lower sensitivity than HCV to sofosbuvir, a nucleotide inhibitor against HCV RdRp, which explained the insusceptibility of HPgV-2 to direct-acting antiviral (DAA) therapy against HCV infection. Our results indicate that HPgV-2 could be an excellent model for studying the mechanisms involved in viral polymerase fidelity as well as RNA virus diversity and evolution. IMPORTANCE RNA viruses represent the most important pathogens for humans and animals and exhibit rapid evolution and high adaptive capacity, which is due to the high mutation rates for using the error-prone RNA-dependent RNA polymerase (RdRp) during replication. The fidelity of RdRp is closely associated with viral diversity, fitness, and pathogenesis. Previous studies have shown that the second human pegivirus (HPgV-2) exhibits a highly conserved genome sequence and low intrahost variation, which might be due to the fidelity of HPgV-2 RdRp. In this work, we used a series of in vitro RNA polymerase assays to evaluate the in vitro fidelity of HPgV-2 RdRp and compared it with that of HCV RdRp. The results indicated that HPgV-2 RdRp preserves significantly higher fidelity than HCV RdRp, which might contribute to the conservation of the HPgV-2 genome. The unique feature of HPgV-2 RdRp fidelity provides a new model for investigation of viral RdRp fidelity.

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The First Nonmammalian Pegivirus Demonstrates Efficient In Vitro Replication and High Lymphotropism.

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