High genetic variability of the group-specific a-determinant of hepatitis B virus surface antigen (HBsAg) and the corresponding fragment of the viral polymerase in chronic virus carriers lacking detectable HBsAg in serum

Abstract

Chronic carriers of hepatitis B virus (HBV) usually show hepatitis B surface antigen (HBsAg) in their sera, which is considered the best marker for acute and chronic HBV infection. In some individuals, however, this antigen cannot be detected by routine serological assays despite the presence of virus in liver and peripheral blood. One reason for this lack of HBsAg might be mutations in the part of the molecule recognized by specific antibodies. To test this hypothesis, the HBV S gene sequences were determined of isolates from 33 virus carriers who were negative for HBsAg but showed antibodies against the virus core (anti-HBc) as the only serological marker of hepatitis B. Isolates from 36 HBsAg-positive patients served as controls. In both groups, a considerable number of novel mutations were found. In isolates from individuals with anti-HBc reactivity only, the variability of the major hydrophilic loop of HBsAg, the main target for neutralizing and diagnostic antibodies, was raised significantly when compared with the residual protein (22. 6 vs 9.4 mutations per 1000 amino acids; P<0.001) and with the corresponding region in the controls (22.6 vs 7.5 exchanges per 1000 residues; P<0.001). A similar hypervariable spot was identified in the reverse transcriptase domain of the viral polymerase, encoded by the same nucleotide sequence in an overlapping reading frame. These findings suggest that at least some of the chronic low-level carriers of HBV, where surface antigen is not detected, could be infected by diagnostic escape mutants and/or by variants with impaired replication.

Genotype, phylogenetic analysis, and transmission pattern of occult hepatitis B virus (HBV) infection in families of asymptomatic HBsAg carriers

“…It has been suggested that increased frequency of mutations in MHL region might contribute to immune escape and occult infection [Weinberger et al, 2000]. Substitutions in the MHL region possibly caused structural changes that contributed to failure of HBsAg detection.…”

“…Studies have shown that the major hydrophilic loop (MHL) of the S gene region of HBsAg negative virus carriers exhibits almost exactly three times as many amino acid exchanges in comparison to the HBsAg positive virus carriers [Weinberger et al, 2000]. This underscores the role of S gene mutations in case of occult infection.…”

A study on sequence variations in pre‐S/surface, X and enhancer II/core promoter/precore regions of occult hepatitis B virus in non‐B, non‐C hepatocellular carcinoma patients in Taiwan

“…7 Any mutation in the pre-S and surface regions may alter HBsAg antigenicity and inhibit anti-HBs production. For example, a single mutation at the ''a'' determinant (amino acid 124-147) of HBsAg can lead to a change in the immunologic epitope, 19,33,34 and mutations or deletion in the pre-S gene can inhibit HBsAg secretion. 35 In addition, because of overlapping of the HBV surface and polymerase genes, the surface gene mutations also caused amino acid mutation in the RT domain of polymerase gene.…”

“…[18][19][20][21] However, the results of these studies have been inconsistent, and some show that most occult HBV are caused by wild-type strains. 7,8,22 Further case control studies are needed to investigate pre-S and surface gene mutations to clarify the absence of detectable HBsAg.…”

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

“…Mutations in the PreS and S sequences have also been reported in HBsAg-negative subjects as possibly affecting other domains of the viral envelope. [35][36][37] Two studies have suggested that different HBV genotypes might be detected in patients with or without detectable serum HBsAg. 37,38 Still, despite the considerable interest of these observations, it is important to note that only a few investigations [39][40][41] provided a complete genome sequence analysis, so that the impact of such mutations on the serologic profile has not been assayed in a completely relevant context.…”