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Journal of Virology, June 2002, p. 5305-5314, Vol. 76, No. 11
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.11.5305-5314.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Immunization with Surface Antigen Vaccine Alone and after Treatment with 1-(2-Fluoro-5-Methyl-ß-L-Arabinofuranosyl)-Uracil (L-FMAU) Breaks Humoral and Cell-Mediated Immune Tolerance in Chronic Woodchuck Hepatitis Virus Infection

Stephan Menne,1* Carol A. Roneker,1 Brent E. Korba,2 John L. Gerin,2 Bud C. Tennant,1 and Paul J. Cote2

Gastrointestinal Unit, Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York,1 Division of Molecular Virology and Immunology, Georgetown University Medical Center, Rockville, Maryland2

Received 18 December 2001/ Accepted 26 February 2002

Woodchucks chronically infected with the woodchuck hepatitis virus (WHV) were treated with the antiviral drug 1-(2-fluoro-5-methyl-ß-L-arabinofuranosyl)-uracil (L-FMAU) or placebo for 32 weeks. Half the woodchucks in each group then received four injections of surface antigen vaccine during the next 16 weeks. Vaccination alone elicited a low-level antibody response to surface antigen in most carriers but did not affect serum WHV DNA and surface antigen. Carriers treated first with L-FMAU to reduce serum WHV DNA and surface antigen and then vaccinated had a similar low-level antibody response to surface antigen. Following vaccinations, cell-mediated immunity to surface antigen was demonstrated in both groups, independent of serum viral and antigen load, but was significantly enhanced in woodchucks treated with L-FMAU and was broadened to include other viral antigens (core, e, and x antigens and selected core peptides). Cell-mediated immunity and antibody responses to surface antigen were observed after drug discontinuation in half of the carriers that received L-FMAU alone. Surface antigen vaccine alone or in combination with drug broke humoral and cell-mediated immune tolerance in chronic WHV infection, but the combination with drug was more effective. This suggested that a high viral and antigen load in carriers is important in maintaining immunologic tolerance during chronicity. The humoral and cellular immunity associated with the combination of L-FMAU and vaccine resembled that observed in self-limited WHV infection. Such combination therapy represents a potentially useful approach to the control of chronic hepatitis B virus infection in humans.

* Corresponding author. Mailing address: Gastrointestinal Unit, Department of Clinical Sciences, College of Veterinary Medicine, Room C-2005 VMC, Cornell University, Ithaca, NY 14853. Phone: (607) 253-3280. Fax: (607) 253-3289. E-mail: sm119{at}cornell.edu.

Journal of Virology, June 2002, p. 5305-5314, Vol. 76, No. 11
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.11.5305-5314.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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