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Journal of Virology, February 2009, p. 1379-1392, Vol. 83, No. 3
0022-538X/09/$08.00+0     doi:10.1128/JVI.01902-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

A Mechanism To Explain the Selection of the Hepatitis e Antigen-Negative Mutant during Chronic Hepatitis B Virus Infection{triangledown}

Lars Frelin,1 Therese Wahlström,1 Amy E. Tucker,1 Joyce Jones,1 Janice Hughes,1 Byung O. Lee,1 Jean-Noel Billaud,1 Cory Peters,1 David Whitacre,1,2 Darrell Peterson,3 and David R. Milich1*

Vaccine Research Institute of San Diego, 3030 Bunker Hill Street, Suite 300, San Diego, California 92109,1 VLP Biotech, Inc., 3030 Bunker Hill Street, Suite 350, San Diego, California 92109,2 Virginia Commonwealth University, Department of Biochemistry, 2-016A, Richmond, VA 232983

Received 9 September 2008/ Accepted 6 November 2008

Hepatitis B virus (HBV) expresses two structural forms of the nucleoprotein, the intracellular nucleocapsid (hepatitis core antigen [HBcAg]) and the secreted nonparticulate form (hepatitis e antigen [HBeAg]). The aim of this study was to evaluate the ability of HBcAg- and HBeAg-specific genetic immunogens to induce HBc/HBeAg-specific CD4+/CD8+ T-cell immune responses and the potential to induce liver injury in HBV-transgenic (Tg) mice. Both the HBcAg- and HBeAg-specific plasmids primed comparable immune responses. Both CD4+ and CD8+ T cells were important for priming/effector functions of HBc/HBeAg-specific cytotoxic T-lymphocyte (CTL) responses. However, a unique two-step immunization protocol was necessary to elicit maximal CTL priming. Genetic vaccination did not prime CTLs in HBe- or HBc/HBeAg-dbl-Tg mice but elicited a weak CTL response in HBcAg-Tg mice. When HBc/HBeAg-specific CTLs were adoptively transferred into HBc-, HBe-, and HBc/HBeAg-dbl-Tg mice, the durations of the liver injury and inflammation were significantly greater in HBeAg-Tg recipient mice than in HBcAg-Tg mice. Importantly, liver injury in HBc/HBeAg-dbl-Tg mice was similar to the injury observed in HBeAg-Tg mice. Loss of HBeAg synthesis commonly occurs during chronic HBV infection; however, the mechanism of selection of HBeAg-negative variants is unknown. The finding that hepatocytes expressing wild-type HBV (containing both HBcAg and HBeAg) are more susceptible to CTL-mediated clearance than hepatocytes expressing only HBcAg suggest that the HBeAg-negative variant may have a selective advantage over wild-type HBV within the livers of patients with chronic infection during an immune response and may represent a CTL escape mutant.

* Corresponding author. Mailing address: Vaccine Research Institute of San Diego, 3030 Bunker Hill Street, Suite 300, San Diego, CA 92109. Phone: (858) 581-3960. Fax: (858) 581-3970. E-mail: dmilich{at}vrisd.org

{triangledown} Published ahead of print on 12 November 2008.

Journal of Virology, February 2009, p. 1379-1392, Vol. 83, No. 3
0022-538X/09/$08.00+0     doi:10.1128/JVI.01902-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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  • Lee, B. O., Tucker, A., Frelin, L., Sallberg, M., Jones, J., Peters, C., Hughes, J., Whitacre, D., Darsow, B., Peterson, D. L., Milich, D. R. (2009). Interaction of the Hepatitis B Core Antigen and the Innate Immune System. J. Immunol. 182: 6670-6681 [Abstract] [Full Text]  


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