Bats are a major natural reservoir for hepaciviruses and pegiviruses

Quan, Phenix‐Lan; Firth, Cadhla; Conte, Juliette M.; Williams, Simon H.; Zambrana‐Torrelio, Carlos; Anthony, Simon J.; Ellison, James A.; Gilbert, Amy T.; Kuzmin, Ivan V.; Niezgoda, Michael; Osinubi, Modupe; Recuenco, Sergio; Markotter, Wanda; Breiman, Robert F.; Kalemba, Lem’s N.; Malekani, Jean; Lindblade, Kim A.; Rostal, Melinda K.; Ojeda-Flores, Rafael; Suzán, Gerardo; Davis, Lora; Blau, Dianna M.; Ogunkoya, Albert; Castillo, Danilo A. Alvarez; Morán, David; Ngam, Sali; Akaibe, Dudu; Agwanda, Bernard; Briese, Thomas; Epstein, Jonathan H.; Daszak, Peter; Rupprecht, Charles E.; Holmes, Edward C.; Lipkin, W. Ian

doi:10.1073/pnas.1303037110

Cited by 260 publications

(264 citation statements)

References 43 publications

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“…At present, there is little consensus over the time-scale of viral origins and their long-term evolutionary dynamics. For instance, the phylogenetic relationships within some groups of primate lentiviruses (Family Retroviridae), pegiviruses and hepaciviruses (Family Flaviviridae) suggest virus-host codivergence [1] or ancient reservoirs in host species [2,3], which can be explained only by evolutionary timeframes of thousands or millions of years. However, many of the time-scales inferred for these viruses using tip-dated molecular clocks are much shorter, on the order of tens or hundreds of years [4,5].…”

Section: Introductionmentioning

confidence: 99%

Analyses of evolutionary dynamics in viruses are hindered by a time-dependent bias in rate estimates

2014

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Time-scales of viral evolution and emergence have been studied widely, but are often poorly understood. Molecular analyses of viral evolutionary timescales generally rely on estimates of rates of nucleotide substitution, which vary by several orders of magnitude depending on the timeframe of measurement. We analysed data from all major groups of viruses and found a strong negative relationship between estimates of nucleotide substitution rate and evolutionary timescale. Strikingly, this relationship was upheld both within and among diverse groups of viruses. A detailed case study of primate lentiviruses revealed that the combined effects of sequence saturation and purifying selection can explain this time-dependent pattern of rate variation. Therefore, our analyses show that studies of evolutionary time-scales in viruses require a reconsideration of substitution rates as a dynamic, rather than as a static, feature of molecular evolution. Improved modelling of viral evolutionary rates has the potential to change our understanding of virus origins.

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Section: Introductionmentioning

confidence: 99%

Analyses of evolutionary dynamics in viruses are hindered by a time-dependent bias in rate estimates

2014

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“…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].…”

Section: Introductionmentioning

confidence: 99%

Discovery of a Novel Human Pegivirus in Blood Associated with Hepatitis C Virus Co-Infection

Berg¹,

Lee²,

Coller³

et al. 2016

Journal of Hepatology

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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 PLOS Pathogens |

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“…Recently, multiple novel animal hepaciviruses naturally infecting various species have been identified (9,10). Viruses classified within the genus Hepacivirus have been discovered in dogs (11) and subsequently in horses (12), rodents (13)(14)(15), bats (16), Old World primates (17), cattle (18), and recently catsharks (19). These viruses display different homologies to HCV and offer new insights into the origin and evolution of Hepaciviruses.…”

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Immune protection against reinfection with nonprimate hepacivirus

Pfaender

Wälter

Grabski

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Hepatitis C virus (HCV) displays a restricted host species tropism and only humans and chimpanzees are susceptible to infection. A robust immunocompetent animal model is still lacking, hampering mechanistic analysis of virus pathogenesis, immune control, and prophylactic vaccine development. The closest homolog of HCV is the equine nonprimate hepacivirus (NPHV), which shares similar features with HCV and thus represents an animal model to study hepacivirus infections in their natural hosts. We aimed to dissect equine immune responses after experimental NPHV infection and conducted challenge experiments to investigate immune protection against secondary NPHV infections. Horses were i.v. injected with NPHV containing plasma. Flow cytometric analysis was used to monitor immune cell frequencies and activation status. All infected horses became viremic after 1 or 2 wk and viremia could be detected in two horses for several weeks followed by a delayed seroconversion and viral clearance. Histopathological examinations of liver biopsies revealed mild, periportally accentuated infiltrations of lymphocytes, macrophages, and plasma cells with some horses displaying subclinical signs of hepatitis. Following viral challenge, an activation of equine immune responses was observed. Importantly, after a primary NPHV infection, horses were protected against rechallenge with the homologous as well as a distinct isolate with only minute amounts of circulating virus being detectable.hepatitis C virus | nonprimate hepacivirus | infection | immune protection | rechallenge H epatitis C virus (HCV) infections constitute a major global health problem with ∼130 million people being chronically infected (1). Once infected, 70-90% of individuals progress to chronicity, rendering HCV the leading cause of liver diseases, including liver fibrosis, cirrhosis, and hepatocellular carcinoma (2). HCV is a blood-borne, positive-stranded RNA virus classified to the family of Flaviviridae within the genus Hepacivirus. Seven different HCV genotypes and numerous subtypes have been described, which differ on the nucleotide level by ∼30-35% between different genotypes and maximally 30% between subtypes (3). Furthermore, within infected individuals the virus circulates as a population of closely related but distinct genomes (4). Recently, significant progress has been made regarding the treatment of HCV with the implementation of direct-acting antiviral (DAA) drugs, which can be administered as all-oral IFN-free therapeutics and should help to reduce the global burden of HCV infections (5). However, there are still many caveats, including high treatment costs and the risk of reinfection after successful therapy, which is a problem especially in patient populations with frequent exposure to HCV. Furthermore, the inadequacy of current HCV screening programs often results in late diagnosis of chronic HCV infection and subsequent proceeding to end-stage liver diseases (6). All of these challenges highlight the necessity for a prophylactic vaccine against HCV, ...

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Bats are a major natural reservoir for hepaciviruses and pegiviruses

Cited by 260 publications

References 43 publications

Analyses of evolutionary dynamics in viruses are hindered by a time-dependent bias in rate estimates

Analyses of evolutionary dynamics in viruses are hindered by a time-dependent bias in rate estimates

Discovery of a Novel Human Pegivirus in Blood Associated with Hepatitis C Virus Co-Infection

Immune protection against reinfection with nonprimate hepacivirus

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