Immunization with surface antigen vaccine alone and after treatment with 1-(2-fluoro-5-methyl-beta-L-arabinofuranosyl)-uracil (L-FMAU) breaks humoral and cell-mediated immune tolerance in chronic woodchuck hepatitis virus infection.
Woodchucks chronically infected with the woodchuck hepatitis virus (WHV) were treated with the antiviral drug 1-(2-fluoro-5-methyl-beta-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.
Menne
Stephan
S
Gastrointestinal Unit, Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA. sm119@cornell.edu
Roneker
Carol A
CA
Korba
Brent E
BE
Gerin
John L
JL
Tennant
Bud C
BC
Cote
Paul J
PJ
D000818:Animals; D000917:Antibody Formation; D000954:Antigens, Surface / Q000276:immunology*; D000956:Antigens, Viral / Q000276:immunology*; D000998:Antiviral Agents / Q000627:therapeutic use*; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives / Q000627:therapeutic use*; D002353:Carrier State; D017325:Hepatitis B Vaccines / Q000276:immunology*; D017919:Hepatitis B Virus, Woodchuck / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control*; D007108:Immune Tolerance / Q000276:immunology*; D007111:Immunity, Cellular; D008392:Marmota; D014611:Vaccination
D000954:Antigens, Surface; D000956:Antigens, Viral; D000998:Antiviral Agents; D017325:Hepatitis B Vaccines; D001086:Arabinofuranosyluracil; C034935:clevudine