Immune response to the pre-S(1) region of the hepatitis B surface antigen (HBsAg): a pre-S(1)-specific T cell response can bypass nonresponsiveness to the pre-S(2) and S regions of HBsAg.
Hepatitis B surface antigen (HBsAg) particles are composed of a major polypeptide, p25, and additional polypeptides of higher m.w., namely p33 and p39, are variably present. All three polypeptides share the 226 amino acid residues of the S region: p33 consists of the p25 sequence plus an NH2-terminal 55 residues (pre-S(2], and p39 consists of the p33 sequence plus an NH2-terminal 108-119 residues (pre-S(1). In previous studies we demonstrated the influence of two Ir genes on the humoral and cellular immune responses to the S region and identified nonresponder phenotypes (H-2f,s). Subsequent studies showed that the immune response to the pre-S(2) region was regulated by H-2-linked genes independently of the S region response, such that immunization of S region nonresponder, pre-(S2) region responder mice (H-2s) with HBsAg/p33 circumvented nonresponse to the S region. In the present study, we have extended this analysis to the pre-S(1) region of HBsAg, with the following results: 1) and pre-S(1) region is immunogenic at the T and B cell levels; 2) anti-pre-S(1) specific antibody production is regulated by H-2-linked genes and can be independent of anti-S and anti-pre-S(2) antibody production; 3) immunization of H-2f strains with HBsAg/p39 particles containing the pre-S(1) region can bypass nonresponsiveness to the S and pre-S(2) regions in terms of antibody production; 4) two synthetic peptides, p32-53 and p94-117, define murine and human antibody binding sites on the pre-S(1) region, and p1-21 and p12-32 define additional human antibody binding sites; 5) pre-S(1)-specific T cells can be elicited in S and pre-S(2) region nonresponder mice (H-2f) and provide functional T cell help for S-pre-S(2)-, and pre-S(1)-specific antibody production; and 6) a T cell recognition site in the pre-S(1) region, p12-32 was identified. These results are relevant to HBV vaccine development, and possibly to viral clearance mechanisms, since the higher m.w. polypeptides are preferentially expressed on intact virions.
Milich
D R
DR
McLachlan
A
A
Chisari
F V
FV
Kent
S B
SB
Thorton
G B
GB
D000208:Acute Disease; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D002472:Cell Transformation, Viral; D000090266:Chromobox Protein Homolog 5; D000939:Epitopes / Q000032:analysis / Q000276:immunology*; D005260:Female; D005838:Genotype; D006183:H-2 Antigens / Q000235:genetics; D006509:Hepatitis B / Q000235:genetics / Q000276:immunology; D006514:Hepatitis B Surface Antigens / Q000032:analysis / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014764:Viral Proteins / Q000032:analysis / Q000276:immunology*; D015678:Viral Structural Proteins
D000914:Antibodies, Viral; C000715594:CBX5 protein, human; D000939:Epitopes; D006183:H-2 Antigens; D006514:Hepatitis B Surface Antigens; D014764:Viral Proteins; D015678:Viral Structural Proteins; D000090266:Chromobox Protein Homolog 5