Improving on the Ability of Endogenous Hepatitis B Core Antigen to Prime Cytotoxic T Lymphocytes

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http://www.journals.uchicago.edu/doi/abs/10.1086/652808

The Journal of Infectious Diseases 2010;201:1867–1879

© 2010 by the Infectious Diseases Society of America. All rights reserved.

0022-1899/2010/20112-0013$15.00

DOI: 10.1086/652808

MAJOR ARTICLE

Improving on the Ability of Endogenous Hepatitis B Core Antigen to Prime

Cytotoxic T Lymphocytes

Nyström,1,a

Antony Chen,1,a

Lars Frelin,1

Gustaf Ahlén,1

Sarene Koh,1,2

Anette Brass,1

Darrell L. ,3

Fons,4

R. Milich,5

Catharina Hultgren,1 and

Matti Sällberg1

1Division of Clinical Microbiology, of Laboratory Medicine, Karolinska

Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden;

2Singapore Institute for Clinical Science, Agency for Science, Technology and

Research, Singapore; 3Virginia Commonwealth University, Richmond; 4Inovio

Biomedical Corporation and 5Vaccine Research Institute of San Diego, San Diego,

California

Hepatitis B virus core antigen (HBcAg) is thought to be a major target for

specific cytotoxic T cells (CTLs) in hepatitis B virus infections. A single dose

of hepatitis C virus nonstructural 3/4A DNA (<5 μg) effectively primes

functional specific CTLs, independently of CD4+ T helper cells and by different

routes of immunization. In contrast, HBcAgâ€specific CTL priming was T helper

cell dependent and highly sensitive to the dose and route of delivery. Although

CTL priming was improved 10â€fold by codon optimization and in vivo

electroporation, low levels of DNA still failed to prime CTLs effectively. Only

high doses (5 μg) of codonâ€optimized HBcAg delivered by in vivo

electroporation primed in vivo lytic and polyfunctional CTLs. The ability of

endogenous HBcAg to prime CTLs is surprisingly inefficient and differs from that

of nonstructural 3/4A. This has important implications for the design of

HBcAgâ€based therapeutic vaccines in humans.

Received 7 July 2009; accepted 18 December 2009; electronically published 6 May

2010.

Reprints or correspondence: Dr Sällberg, Div of Clinical Microbiology,

Karolinska Institutet, Karolinska University Hospital Huddinge, Sâ€141 86

Stockholm, Sweden (matti.sallberg@...).

Potential conflicts of interest: none reported.

Financial support: Swedish Cancer Foundation; Swedish Research Council (grants

to M.S.); and Swedish Society of Medical Research, Swedish Society of Medicine,

Royal Swedish Academy of Sciences, Foundation Längmanska Kulturfonden, Goljes

Memorial Fund, Swedish Foundation for Research and Development in Medical

Microbiology, and Karolinska Institutet (grants to L.F.).

aJ.N. and A.C. contributed equally to this work

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