Characterization of Marmoset Hepatitis Virus

Parks, Wade P.; Melnick, Joseph L.; Voss, William R.; Singer, Don B.; Rosenberg, Harvey S.; Alcott, Judith; Casazzat, Anna M.

doi:10.1093/infdis/120.5.548

Cited by 38 publications

(20 citation statements)

References 17 publications

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“…These results are contrary to those in early reports in the literature (24,25) that suggested that GB virus infections were confined to tamarins. However, the advent of sensitive, specific real-time PCR, which can quantitate serum virus RNA, has conclusively demonstrated that GBV-B replicates in the common marmoset, as previously reported by Bright et al (17).…”

Section: Discussioncontrasting

confidence: 99%

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Development of a GB Virus B Marmoset Model and Its Validation with a Novel Series of Hepatitis C Virus NS3 Protease Inhibitors

Bright

Carroll

Watts

et al. 2004

J Virol

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GB virus B (GBV-B), a flavivirus closely related to HCV, has previously been shown to infect and replicate to high titers in tamarins (Saguinus sp.). This study describes the use of GBV-B infection and replication in the common marmoset (Callithrix jacchus) for the successful development and validation of a surrogate animal model for hepatitis C virus (HCV). Infection of marmosets with GBV-B produced a viremia that peaked at 108 to 10 9 genome copies/ml for a period of 40 to 60 days followed by viral clearance at 60 to 80 days postinfection. Passage of the initial tamarin-derived GBV-B in marmosets produced an infectious stock that gave a more reproducible and consistent infection in the marmoset. Titration of the virus stocks in vivo indicated that they contained 1 infectious unit for every 1,000 genome copies. Cultures of primary marmoset hepatocytes were also successfully infected with GBV-B, with high levels of virus detected in supernatants and cells for up to 14 days postinfection. Treatment of GBV-B-infected hepatocyte cultures with a novel class of HCV protease inhibitor (pyrrolidine 5,5 trans-lactams) reduced viral levels by more than 2 logs. Treatment of GBV-B-infected marmosets with one such inhibitor resulted in a 3-log drop in serum viral titer over 4 days of therapy. These studies provide the first demonstration of the in vivo efficacy of a small-molecule inhibitor for HCV in an animal model and illustrate the utility of GBV-B as a surrogate animal model system for HCV.For many years the discovery and development of novel therapies for hepatitis C virus (HCV) has been hampered by a lack of both a small animal model and a robust in vitro viral replication system. Although the recently developed HCV replicon system (3, 20) has proven extremely valuable for preclinical testing of antiviral compounds, there is still a need for virus-based culture systems and animal models. The restricted host range of HCV means that apart from humans, it will only infect chimpanzees. However, ethical considerations and cost mitigate the use of chimpanzees in drug discovery programs. HCV murine models in which transgenic or mutant mice implanted with human hepatocytes were found to be able to support the replication of HCV have been described previously (16,21). However, these systems are laborious, require specialist expertise, and have yet to be reproduced. In the absence of an HCV animal model, researchers have looked to surrogate viruses (in particular, GB virus B [GBV-B]) to provide an alternative model system. GBV-B was first described over 30 years ago, following the inoculation of tamarins with sera from a patient suffering from acute hepatitis. Serial passage of sera from these animals into further tamarins resulted in hepatitis. Although initially thought to be a human pathogen, this "GB agent" is now known to be of primate origin (9). When the molecular sequence of the GB agent was first characterized, two separate but closely related viruses, GBV-A and GBV-B, were identified (22, 32). GBV-A appears to replic...

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Section: Discussioncontrasting

confidence: 99%

“…However, captive-bred tamarins are difficult to source, breed, and handle. Literature reports in the 1970s suggested that GBV-B had a very restricted host range and could only replicate in tamarins (24,25). More recently, however, GBV-B has been shown to replicate in owl monkeys, which are members of the Cebidae family of New World monkeys (9).…”

mentioning

confidence: 99%

Development of a GB Virus B Marmoset Model and Its Validation with a Novel Series of Hepatitis C Virus NS3 Protease Inhibitors

Bright

Carroll

Watts

et al. 2004

J Virol

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“…Passage of this "GB agent" in the Sanguinus sp. (tamarins) allowed extensive virological characterization (2)(3)(4). However, subsequent primate host range and crosschallenge experiments suggested that the GB agent was distinct from the currently known human hepatitis viruses (3)(4)(5)(6)(7)(8)(9)(10)(11).…”

mentioning

confidence: 99%

Identification of two flavivirus-like genomes in the GB hepatitis agent.

Simons

Pilot‐Matias

Leary

et al. 1995

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

519

337

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A subtractive PCR methodology known as representational difference analysis was used to clone specific nucleotide sequences present in the infectious plasma from a tamarin infected with the GB hepatitis agent. Eleven unique clones were identified, seven of which were examined extensively. All seven clones appeared to be derived from sequences exogenous to the genomes of humans, tamarins, Saccharomyces cerevisiae, and Escherichia coli. In addition, sequences from these clones were not detected in plasma or liver tissue of tamarins prior to their inoculation with the GB agent. These sequences were detected by reverse transcription-PCR in acute-phase plasma of tamarins inoculated with the GB agent. Probes derived from two of the seven clones detected an RNA species of .8.3 kb in the liver of a GB-agent-infected tamarin by Northern blot hybridization. Sequence analysis indicated that five of the seven clones encode polypeptides that possess limited amino acid identity with the nonstructural proteins of hepatitis C virus. Extension of the sequences found in the seven clones revealed that plasma from an infected tamarin contained two RNA molecules >9 kb long. Limited sequence identity with various isolates of hepatitis C virus and the relative positions of putative RNA helicases and RNAdependent RNA polymerases in the predicted protein products of these molecules suggested that the GB agent contains two unique flavivirus-like genomes.

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“…(65) induced disease with human specimens other than GB and it is of particular interest to note that the MS-1 virus of Willow Brook [11] consistently induced disease in 4 separate experiments by our group [10], by Bang and Hillis [1] at John Hopkins School of Medicine, Baltimore, and by Kirschstein's laboratory at the National Insti tutes of Health, Division of Biological Standards [13] whereas control marmosets exhibited no disease. Somewhat different results were obtained by Melnick's group [16,17]. They reported that spontane ous hepatitis occurred almost regularly in their marmosets but the disease described by them differs from the histopathology closely resembling human viral hepatitis observed in inoculated marmosets us and other investigators.…”

Section: Transmission Of Disease To Marmosetsmentioning

confidence: 77%