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Journal of Virology, September 2002, p. 8609-8620, Vol. 76, No. 17
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.17.8609-8620.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Immunogenicity and Tolerogenicity of Hepatitis B Virus Structural and Nonstructural Proteins: Implications for Immunotherapy of Persistent Viral Infections{dagger}

Kazuhiro Kakimi,1,2 Masanori Isogawa,1 JoSan Chung,1 Alessandro Sette,3 and Francis V. Chisari1*

Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037,1 Epimmune, Inc., San Diego, California 92121,3 Fourth Department of Internal Medicine, Tokyo Medical University, Tokyo 160-0023, Japan2

Received 15 January 2002/ Accepted 7 June 2002

Persistent hepatitis B virus (HBV) infection is characterized by a weak and narrowly focused CD8+ T-cell response to HBV that is thought to reflect the induction of central and/or peripheral tolerance to HBV proteins in neonatal and adult onset infections, respectively. Immunotherapeutic strategies that overcome tolerance and boost these suboptimal responses may lead to viral clearance in chronically infected individuals. The present study was performed to compare the relative immunogenicities and tolerogenicities of HBV structural (envelope [ENV]) and nonstructural (polymerase [POL]) proteins at the CD8+ cytotoxic T lymphocyte (CTL) level in transgenic mice that replicate HBV in the liver and secrete infectious virus into the blood, thus representing an excellent model of persistent HBV infection. Interestingly, the mice were tolerant to the ENV but not to the POL proteins at the CTL level. Furthermore, the POL-specific CTLs had no impact on HBV replication or liver function in vivo, even though they were readily induced and reached the liver after DNA immunization, reflecting their relatively low avidity and the low level at which the POL protein is expressed by the hepatocyte. Collectively, these results suggest that the factors that make POL less tolerogenic also make POL-specific CTLs relatively inefficient effector cells when they reach the target organ. Immunotherapeutic strategies to control HBV infection by inducing virus-specific CTL responses in chronically infected subjects should be evaluated in light of this observation.

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

{dagger} This is manuscript number 14261-MEM from the Scripps Research Institute.

Journal of Virology, September 2002, p. 8609-8620, Vol. 76, No. 17
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.17.8609-8620.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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