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Journal of Virology, August 2008, p. 8183-8195, Vol. 82, No. 16
0022-538X/08/$08.00+0 doi:10.1128/JVI.00142-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
Previously Infected Chimpanzees Are Not Consistently Protected against Reinfection or Persistent Infection after Reexposure to the Identical Hepatitis C Virus Strain
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Jens Bukh,1,2*
Robert Thimme,3
Jean-Christophe Meunier,1
Kristina Faulk,1
Hans Christian Spangenberg,3
Kyong-Mi Chang,3
William Satterfield,4
Francis V. Chisari,3 and
Robert H. Purcell1
Hepatitis Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892,1 Copenhagen Hepatitis C Program, Department of Infectious Diseases and Clinical Research Centre, Copenhagen University Hospital, DK-2650 Hvidovre, and Department of International Health, Immunology and Microbiology, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark,2 Division of Experimental Pathology, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037,3 Department of Veterinary Sciences, Michale E. Keeling Center for Comparative Medicine and Research, M. D. Anderson Cancer Center, Bastrop, Texas 786024
Received 18 January 2008/ Accepted 31 May 2008
Protective immunity after resolved hepatitis C virus (HCV) infection has been reported. However, the breadth of this immunity has remained controversial, and the role of neutralizing antibodies has not been well-defined. In the present study, two chimpanzees (CH96A008 and CH1494) with resolved monoclonal H77C (genotype 1a) infection were rechallenged with low-dose homologous H77C virus about 12 months after viral clearance; CH96A008 became persistently infected, and CH1494 had transient viremia lasting 2 weeks. CH1494 was subsequently either partially or completely protected following five homologous rechallenges with monoclonal H77C or polyclonal H77 and after six heterologous rechallenges with HC-J4 (genotype 1b) or HC-J6 (genotype 2a) viruses. Subsequently, a final challenge with H77C resulted in persistent HCV infection. In both chimpanzees, serum neutralizing antibodies against retroviral pseudoparticles bearing the H77C envelope proteins were not detected during the initial infection or during rechallenge. However, anamnestic cellular immune responses developed during the initial homologous rechallenge, in particular in CH96A008, which developed a persistent infection. Polyprotein sequences of viruses recovered from CH1494 after the two homologous rechallenges that resulted in transient viremia were identical with the H77C virus. In contrast, the polyprotein sequences of viruses recovered from both chimpanzees after homologous rechallenge resulting in persistent infection had numerous changes. These findings have important implications for our understanding of immunity against HCV; even in the best-case scenario with autologous rechallenge, low-level viral persistence was seen in the presence of primed T-cell responses.
* Corresponding author. Mailing address: Hepatitis Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 50, Room 6531, 50 South Dr., MSC 8009, Bethesda, MD 20892-8009. Phone: 45 36 32 63 80. Fax: (301) 402-0524. E-mail: jbukh{at}niaid.nih.gov
Published ahead of print on 11 June 2008.
Supplemental material for this article may be found at http://jvi.asm.org/.
Journal of Virology, August 2008, p. 8183-8195, Vol. 82, No. 16
0022-538X/08/$08.00+0 doi:10.1128/JVI.00142-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
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