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Journal of Virology, October 2009, p. 9652-9662, Vol. 83, No. 19
0022-538X/09/$08.00+0     doi:10.1128/JVI.00867-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Size of the Viral Inoculum Contributes to the Outcome of Hepatitis B Virus Infection{triangledown} ,{dagger}

Shinichi Asabe,1 Stefan F. Wieland,1 Pratip K. Chattopadhyay,2 Mario Roederer,2 Ronald E. Engle,3 Robert H. Purcell,3 and Francis V. Chisari1*

Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037,1 Immuno Technology Section, Laboratory of Immunology, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892,2 Hepatitis Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 208923

Received 30 April 2009/ Accepted 13 July 2009

The impact of virus dose on the outcome of infection is poorly understood. In this study we show that, for hepatitis B virus (HBV), the size of the inoculum contributes to the kinetics of viral spread and immunological priming, which then determine the outcome of infection. Adult chimpanzees were infected with a serially diluted monoclonal HBV inoculum. Unexpectedly, despite vastly different viral kinetics, both high-dose inocula (1010 genome equivalents [GE] per animal) and low-dose inocula (10° GE per animal) primed the CD4 T-cell response after logarithmic spread was detectable, allowing infection of 100% of hepatocytes and requiring prolonged immunopathology before clearance occurred. In contrast, intermediate (107 and 104 GE) inocula primed the T-cell response before detectable logarithmic spread and were abruptly terminated with minimal immunopathology before 0.1% of hepatocytes were infected. Surprisingly, a dosage of 101 GE primed the T-cell response after all hepatocytes were infected and caused either prolonged or persistent infection with severe immunopathology. Finally, CD4 T-cell depletion before inoculation of a normally rapidly controlled inoculum precluded T-cell priming and caused persistent infection with minimal immunopathology. These results suggest that the relationship between the kinetics of viral spread and CD4 T-cell priming determines the outcome of HBV infection.

* Corresponding author. Mailing address: The Scripps Reserach Institute, SBR-10, 10550 North Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-8228. Fax: (858) 784-2160. E-mail: fchisari{at}scripps.edu

{triangledown} Published ahead of print on 22 July 2009.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, October 2009, p. 9652-9662, Vol. 83, No. 19
0022-538X/09/$08.00+0     doi:10.1128/JVI.00867-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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