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Journal of Virology, August 2009, p. 8062-8075, Vol. 83, No. 16
0022-538X/09/$08.00+0     doi:10.1128/JVI.00032-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Lack of Adaptation of Chimeric GB Virus B/Hepatitis C Virus in the Marmoset Model: Possible Effects of Bottleneck {triangledown}

Trudie Weatherford,1,3 Deborah Chavez,1 Kathleen M. Brasky,2 Stanley M. Lemon,4 Annette Martin,5 and Robert E. Lanford1,2,3*

Department of Virology and Immunology, Southwest Foundation for Biomedical Research,1 Southwest National Primate Research Center, 7620 N.W. Loop 410, San Antonio, Texas 78227,2 Department of Microbiology and Immunology, University of Texas Health Science Center, 7703 Floyd Curl Dr., San Antonio, Texas 78229,3 Institute for Human Infections and Immunity and Department of Microbiology and Immunology, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555,4 Unité de Génétique Moléculaire des Virus à ARN, URA CNRS 3015, Institut Pasteur, 75724 Paris Cedex 15, France5

Received 7 January 2009/ Accepted 20 May 2009

Approximately 3% of the world population is chronically infected with hepatitis C virus (HCV). GB virus B (GBV-B), a surrogate model for HCV, causes hepatitis in tamarins and is the virus phylogenetically most closely related to HCV. Previously we described a chimeric GBV-B containing an HCV insert from the 5' noncoding region (NCR) that was adapted for efficient replication in tamarins (Saguinus species). We have also demonstrated that wild-type (WT) GBV-B rapidly adapts for efficient replication in a closely related species, the common marmoset (Callithrix jacchus). Here, we demonstrate that the chimeric virus failed to adapt during serial passage in marmosets. The chimeric virus was passaged four times through 24 marmosets. During passage, two marmoset phenotypes were observed: susceptible and partially resistant. Although appearing to adapt in a resistant animal during a prolonged and gradual increase in viremia, the chimeric GBV-B failed to replicate efficiently upon passage to a naïve marmoset. The resistance was specific to the chimeric virus, as the chimeric virus-resistant animals were susceptible to marmoset-adapted WT virus during rechallenge studies. Three isolates of the chimeric virus were sequenced, and 20 nucleotide changes were observed, including eight amino acid changes. Three unique changes were observed in the 5' NCR chimeric insert, an area that is highly conserved in HCV. We speculate that the failure of the chimeric virus to adapt in marmosets might be due to a bottleneck that occurs at the time of infection of resistant animals, which may lead to a loss of fitness upon serial passage.

* Corresponding author. Mailing address: Department of Virology and Immunology, Southwest Foundation for Biomedical Research, 7620 N.W. Loop 410, San Antonio, TX 78227. Phone: (210) 258-9445. Fax: (210) 670-3329. E-mail: rlanford{at}icarus.sfbr.org

{triangledown} Published ahead of print on 27 May 2009.

Journal of Virology, August 2009, p. 8062-8075, Vol. 83, No. 16
0022-538X/09/$08.00+0     doi:10.1128/JVI.00032-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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