A Novel Hepacivirus with an Unusually Long and Intrinsically Disordered NS5A Protein in a Wild Old World Primate

Lauck, Michael; Sibley, Samuel D.; Lara, James; Purdy, Michael A.; Khudyakov, Yury; Holzmann, David; Tumukunde, Alex; Weny, Geoffrey; Switzer, William M.; Chapman, Colin A.; Hughes, Austin L.; Friedrich, Thomas C.; O’Connor, David H.; Goldberg, Tony L.

doi:10.1128/jvi.00888-13

Cited by 89 publications

(86 citation statements)

References 70 publications

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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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confidence: 99%

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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confidence: 99%

Immune protection against reinfection with nonprimate hepacivirus

Pfaender

Wälter

Grabski

et al. 2017

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

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“…Tissue tropism and disease association remain largely uncharacterized. Subsequently, hepaciviruses have also been discovered in rodents (6,9), bats (10), and Old World primates (11). Pegiviruses are closely related to hepaciviruses and include human (HPgV/ GBV-C) and simian (SPgV/GBV-A) pegiviruses, none of which are associated with disease (12).…”

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confidence: 99%

Characterization of nonprimate hepacivirus and construction of a functional molecular clone

Scheel

Kapoor

Nishiuchi

et al. 2015

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

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Nonprimate hepacivirus (NPHV) is the closest known relative of hepatitis C virus (HCV) and its study could enrich our understanding of HCV evolution, immunity, and pathogenesis. High seropositivity is found in horses worldwide with ∼3% viremic. NPHV natural history and molecular virology remain largely unexplored, however. Here, we show that NPHV, like HCV, can cause persistent infection for over a decade, with high titers and negative strand RNA in the liver. NPHV is a near-universal contaminant of commercial horse sera for cell culture. The complete NPHV 3′-UTR was determined and consists of interspersed homopolymer tracts and an HCV-like 3′-terminal poly(U)-X-tail. NPHV translation is stimulated by miR-122 and the 3′-UTR and, similar to HCV, the NPHV NS3-4A protease can cleave mitochondrial antiviral-signaling protein to inactivate the retinoic acid-inducible gene I pathway. Using an NPHV consensus cDNA clone, replication was not observed in primary equine fetal liver cultures or after electroporation of selectable replicons. However, intrahepatic RNA inoculation of a horse initiated infection, yielding high RNA titers in the serum and liver. Delayed seroconversion, slightly elevated circulating liver enzymes and mild hepatitis was observed, followed by viral clearance. This establishes the molecular components of a functional NPHV genome. Thus, NPHV appears to resemble HCV not only in genome structure but also in its ability to establish chronic infection with delayed seroconversion and hepatitis. This NPHV infectious clone and resulting acute phase sera will facilitate more detailed studies on the natural history, pathogenesis, and immunity of this novel hepacivirus in its natural host.hepatitis C virus | infectious cDNA clone | equine liver disease | animal model | 3′-untranslated region

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“…Our discovery of novel pegiviruses and simian arteriviruses in AGMs in Zambia and South Africa adds to an emerging theme: with few exceptions (43), the plasma RNA virome of African mon- keys is a distinct and definable entity consisting of various combinations of simian immunodeficiency viruses, simian pegiviruses, and simian arteriviruses. To date, species-specific simian pegiviruses and simian arteriviruses have been found in cercopithecoid monkeys belonging to both major African subfamilies (i.e., Cercopithecinae and Colobinae) and both cercopithecine tribes (i.e., Cercopithecini and Papionini).…”

Section: Discussionmentioning

confidence: 99%

Arteriviruses, Pegiviruses, and Lentiviruses Are Common among Wild African Monkeys

Bailey

Lauck

Ghai

et al. 2016

J Virol

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Nonhuman primates (NHPs) are a historically important source of zoonotic viruses and are a gold-standard model for research on many human pathogens. However, with the exception of simian immunodeficiency virus (SIV) (family Retroviridae), the blood-borne viruses harbored by these animals in the wild remain incompletely characterized. Here, we report the discovery and characterization of two novel simian pegiviruses (family Flaviviridae) and two novel simian arteriviruses (family Arteriviridae) in wild African green monkeys from Zambia (malbroucks [Chlorocebus cynosuros]) and South Africa (vervet monkeys [Chlorocebus pygerythrus]). We examine several aspects of infection, including viral load, genetic diversity, evolution, and geographic distribution, as well as host factors such as age, sex, and plasma cytokines. In combination with previous efforts to characterize blood-borne RNA viruses in wild primates across sub-Saharan Africa, these discoveries demonstrate that in addition to SIV, simian pegiviruses and simian arteriviruses are widespread and prevalent among many African cercopithecoid (i.e., Old World) monkeys. IMPORTANCEPrimates are an important source of viruses that infect humans and serve as an important laboratory model of human virus infection. Here, we discover two new viruses in African green monkeys from Zambia and South Africa. In combination with previous virus discovery efforts, this finding suggests that these virus types are widespread among African monkeys. Our analysis suggests that one of these virus types, the simian arteriviruses, may have the potential to jump between different primate species and cause disease. In contrast, the other virus type, the pegiviruses, are thought to reduce the disease caused by human immunodeficiency virus (HIV) in humans. However, we did not observe a similar protective effect in SIV-infected African monkeys coinfected with pegiviruses, possibly because SIV causes little to no disease in these hosts.

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A Novel Hepacivirus with an Unusually Long and Intrinsically Disordered NS5A Protein in a Wild Old World Primate

Cited by 89 publications

References 70 publications

Immune protection against reinfection with nonprimate hepacivirus

Immune protection against reinfection with nonprimate hepacivirus

Characterization of nonprimate hepacivirus and construction of a functional molecular clone

Arteriviruses, Pegiviruses, and Lentiviruses Are Common among Wild African Monkeys

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