Characterization of Unusual Escape Variants of Hepatitis B Virus Isolated from a Hepatitis B Surface Antigen-Negative Subject

Abstract

Hepatitis B virus DNA was extracted from serial serum samples of a hepatitis B surface antigen-negative patient with antibodies to the core protein as the only marker of an infection with hepatitis B virus. This patient showed no symptoms of hepatic injury. Sequencing of the amplified viral DNA demonstrated multiple amino acid changes clustering in surface-exposed regions of the surface protein. Synthesis and association of the middle (M) and small (S) surface proteins could be shown in vitro. The variant surface antigens were recognized neither by monoclonal antibodies to the surface antigen nor by the vaccinee’s sera. Consequences for hepatitis B surface antigen testing and vaccine development are discussed.

Characterization of the reactivity pattern of murine monoclonal antibodies against wild-type hepatitis B surface antigen to g145r and other naturally occurring “a” loop escape mutations

“…12,35 Diagnosis failure has been associated with surface gene mutations, including G145R. 39,52 HBsAg missed with polyclonal antibody-based assays had novel or very rare mutants within the central region. 14 Because protection against HBV infection correlates to the appearance or administration of anti-HBs antibodies, changed antigenicity of surface mutants affects most clinical aspects of hepatitis B: chronicity, vaccine efficacy, effectiveness of HBIg immunoprophylaxis posttransplantation, and diagnostic accuracy.…”

Persistent hepatitis B virus infection in subjects without hepatitis B surface antigen: Clinically significant or purely “occult”?

“…Thus, mutations in the S gene have been described that could account for negative serologic assays for HBsAg. [32][33][34] Mutations have also been observed in the "escape variants" described after HBV vaccination (reviews in Carman et al, 29 Brunetto et al, 30 and Zuckerman and Zuckerman 31 ). Mutations in the PreS and S sequences have also been reported in HBsAg-negative subjects as possibly affecting other domains of the viral envelope.…”

Occult hepatitis B virus infection: implications in transfusion

“…Weinberger et al [46] < 1 × 10 4 geq (median 5·0 × 10 2 ) Grethe et al [37] 1 × 10 2 −1 × 10 3 geq Yotsuyanagi et al [31] < 1 × 10 3 geq Hennig et al [13] 1000, 15, 5 IU Jilg et al [68] 100-10 000 copies Kessler et al [67] 400-4 × 10 5 copies (median 7·0 × 10 3 ) Weber et al a [69] 8·0 × 10 2 −4·0 × 10 6 copies Noborg et al [30] 100-711 copies 263-646 copies Saito et al [47] < 1 × 10 3 copies a In a mixture of patients of different origins, some with liver disease. Anti-HBc, antibody to hepatitis B core antigen; anti-HBs, antibody to hepatitis B surface antigen; geq, genome equivalents.…”