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Science 30 April 1999:
Vol. 284. no. 5415, pp. 825 - 829
DOI: 10.1126/science.284.5415.825
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Reports

Viral Clearance Without Destruction of Infected Cells During Acute HBV Infection

Luca G. Guidotti, 1 Rosemary Rochford, 2 Josan Chung, 1 Max Shapiro, 3 Robert Purcell, 4 Francis V. Chisari 1*

Viral clearance during hepatitis B virus (HBV) infection has been thought to reflect the destruction of infected hepatocytes by CD8+ T lymphocytes. However, in this study, HBV DNA was shown to largely disappear from the liver and the blood of acutely infected chimpanzees long before the peak of T cell infiltration and most of the liver disease. These results demonstrate that noncytopathic antiviral mechanisms contribute to viral clearance during acute viral hepatitis by purging HBV replicative intermediates from the cytoplasm and covalently closed circular viral DNA from the nucleus of infected cells.

1 Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
2 Department of Epidemiology, University of Michigan, Ann Arbor, MI 48109-2029, USA.
3 Bioqual, Incorporated, Rockville, MD 20850, USA.
4 The National Institutes of Health, Bethesda, MD 20892, USA.
*   To whom correspondence should be addressed. E-mail: fchisari{at}scripps.edu

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Blocking Chemokine Responsive to {gamma}-2/Interferon (IFN)-{gamma} Inducible Protein and Monokine Induced by IFN-{gamma} Activity In Vivo Reduces the Pathogenetic but not the Antiviral Potential of Hepatitis B Virus-specific Cytotoxic T Lymphocytes.
K. Kakimi, T. E. Lane, S. Wieland, V. C. Asensio, I. L. Campbell, F. V. Chisari, and L. G. Guidotti (2001)
J. Exp. Med. 194, 1755-1766
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In Vivo Inhibition of Anti-Hepatitis B Virus Core Antigen (HBcAg) Immunoglobulin G Production by HBcAg-Specific CD4+ Th1-Type T-Cell Clones in a hu-PBL-NOD/SCID Mouse Model.
T. Cao, P. Meuleman, I. Desombere, M. Sallberg, and G. Leroux-Roels (2001)
J. Virol. 75, 11449-11456
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Selective Loss of Natural Killer T Cells by Apoptosis following Infection with Lymphocytic Choriomeningitis Virus.
J. A. Hobbs, S. Cho, T. J. Roberts, V. Sriram, J. Zhang, M. Xu, and R. R. Brutkiewicz (2001)
J. Virol. 75, 10746-10754
   Abstract »    Full Text »    PDF »
Determinants of Viral Clearance and Persistence during Acute Hepatitis C Virus Infection.
R. Thimme, D. Oldach, K.-M. Chang, C. Steiger, S. C. Ray, and F. V. Chisari (2001)
J. Exp. Med. 194, 1395-1406
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Antiviral Actions of Interferons.
C. E. Samuel (2001)
Clin. Microbiol. Rev. 14, 778-809
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Critical Role for Alpha/Beta and Gamma Interferons in Persistence of Lymphocytic Choriomeningitis Virus by Clonal Exhaustion of Cytotoxic T Cells.
R. Ou, S. Zhou, L. Huang, and D. Moskophidis (2001)
J. Virol. 75, 8407-8423
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Perforin and Fas in murine gammaherpesvirus-specific CD8+ T cell control and morbidity.
D. J. Topham, R. C. Cardin, J. P. Christensen, J. W. Brooks, G. T. Belz, and P. C. Doherty (2001)
J. Gen. Virol. 82, 1971-1981
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DNA Microarray Analysis of Chimpanzee Liver during Acute Resolving Hepatitis C Virus Infection.
C. B. Bigger, K. M. Brasky, and R. E. Lanford (2001)
J. Virol. 75, 7059-7066
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Interferon-gamma -Mediated Site-Specific Clearance of Alphavirus from CNS Neurons.
G. K. Binder and D. E. Griffin (2001)
Science 293, 303-306
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Sustained Dysfunction of Antiviral CD8+ T Lymphocytes after Infection with Hepatitis C Virus.
N. H. Gruener, F. Lechner, M.-C. Jung, H. Diepolder, T. Gerlach, G. Lauer, B. Walker, J. Sullivan, R. Phillips, G. R. Pape, et al. (2001)
J. Virol. 75, 5550-5558
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Transfer of Hepatitis B Virus Genome by Adenovirus Vectors into Cultured Cells and Mice: Crossing the Species Barrier.
M. F. Sprinzl, H. Oberwinkler, H. Schaller, and U. Protzer (2001)
J. Virol. 75, 5108-5118
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Three Different Vaccines Based on the 140-Amino Acid MUC1 Peptide with Seven Tandemly Repeated Tumor-Specific Epitopes Elicit Distinct Immune Effector Mechanisms in Wild-Type Versus MUC1-Transgenic Mice with Different Potential for Tumor Rejection.
M. M. Soares, V. Mehta, and O. J. Finn (2001)
J. Immunol. 166, 6555-6563
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Kinetics of Acute Hepatitis B Virus Infection in Humans.
S. A. Whalley, J. M. Murray, D. Brown, G. J.M. Webster, V. C. Emery, G. M. Dusheiko, and A. S. Perelson (2001)
J. Exp. Med. 193, 847-854
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Impairment of CD4+ T Cell Responses during Chronic Virus Infection Prevents Neutralizing Antibody Responses against Virus Escape Mutants.
A. Ciurea, L. Hunziker, P. Klenerman, H. Hengartner, and R. M. Zinkernagel (2001)
J. Exp. Med. 193, 297-306
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Role of Interleukin-4 (IL-4), IL-12, and Gamma Interferon in Primary and Vaccine-Primed Immune Responses to Friend Retrovirus Infection.
U. Dittmer, K. E. Peterson, R. Messer, I. M. Stromnes, B. Race, and K. J. Hasenkrug (2001)
J. Virol. 75, 654-660
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Overcoming T Cell Tolerance to the Hepatitis B Virus Surface Antigen in Hepatitis B Virus-Transgenic Mice.
A. D. Sette, C. Oseroff, J. Sidney, J. Alexander, R. W. Chesnut, K. Kakimi, L. G. Guidotti, and F. V. Chisari (2001)
J. Immunol. 166, 1389-1397
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CD4+ T Cells and Gamma Interferon in the Long-Term Control of Persistent Friend Retrovirus Infection.
M. Iwashiro, K. Peterson, R. J. Messer, I. M. Stromnes, and K. J. Hasenkrug (2001)
J. Virol. 75, 52-60
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Kinetics of Hepadnavirus Loss from the Liver during Inhibition of Viral DNA Synthesis.
Y. Zhu, T. Yamamoto, J. Cullen, J. Saputelli, C. E. Aldrich, D. S. Miller, S. Litwin, P. A. Furman, A. R. Jilbert, and W. S. Mason (2001)
J. Virol. 75, 311-322
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Combination Therapy with Lamivudine and Adenovirus Causes Transient Suppression of Chronic Woodchuck Hepatitis Virus Infections.
T. Zhou, J.-T. Guo, F. A. Nunes, K. L. Molnar-Kimber, J. M. Wilson, C. E. Aldrich, J. Saputelli, S. Litwin, L. D. Condreay, C. Seeger, et al. (2000)
J. Virol. 74, 11754-11763
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DNA Vaccines Encoding Interleukin-8 and RANTES Enhance Antigen-Specific Th1-Type CD4+ T-Cell-Mediated Protective Immunity against Herpes Simplex Virus Type 2 In Vivo.
J.-I. Sin, J. J. Kim, C. Pachuk, C. Satishchandran, and D. B. Weiner (2000)
J. Virol. 74, 11173-11180
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Hepatitis C virus lacking the hypervariable region 1 of the second envelope protein is infectious and causes acute resolving or persistent infection in chimpanzees.
X. Forns, R. Thimme, S. Govindarajan, S. U. Emerson, R. H. Purcell, F. V. Chisari, and J. Bukh (2000)
PNAS
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Induction of Vigorous Helper and Cytotoxic T Cell as well as B Cell Responses by Dendritic Cells Expressing a Modified Antigen Targeting Receptor-Mediated Internalization Pathway.
Z. You, X. F. Huang, J. Hester, L. Rollins, C. Rooney, and S.-Y. Chen (2000)
J. Immunol. 165, 4581-4591
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