Naturally occurring escape mutants of hepatitis B virus with various mutations in the S gene in carriers seropositive for antibody to hepatitis B surface antigen

Abstract

Hepatitis B virus (HBV) DNA was extracted from sera of six carriers with hepatitis B e antigen as well as antibody to hepatitis B surface antigen and sequenced within the pre-S regions and the S gene. HBV DNA clones from five of these carriers had point mutations in the S gene, resulting in conversion from Ile-126 or Thr-126 of the wild-type virus to Ser-126 or Asn-126 in three carriers and conversion from Gly-145 to Arg-145 in three of them; clones with Asn-126 or Arg-145 were found in one carrier. All 12 clones from the other carrier had an insertion of 24 bp encoding an additional eight amino acids between Thr-123 and Cys-124. In addition, all or at least some of the HBV DNA clones from these carriers had in-phase deletions in the 5' terminus of the pre-S2 region. These results indicate that HBV escape mutants with mutations in the S gene affecting the expression of group-specific determinants would survive in some carriers after they seroconvert to antibody against surface antigen. Carriers with HBV escape mutants may transmit HBV either by donation of blood units without detectable surface antigen or through community-acquired infection, which would hardly be prevented by current hepatitis B immuneglobulin or vaccines.

Licensed recombinant hepatitis B vaccines protect chimpanzees against infection with the prototype surface gene mutant of hepatitis B virus

“…Our results do not address the issue of other HBV S gene mutants. Among a number of HBV variants with amino acid mutations in the a determinant, 2-31,72-77 those identified in relation to immunoprophylaxis, 2-27 coexisting anti-HBs, [28][29][30][31] or inability to detect HBsAg by several assays [72][73][74][75][76] may have weak avidity to anti-HBs, and several such variants have been demonstrated in vitro to have a reduced binding affinity for anti-HBs. 5,13,18,26,27,42,73 However, the protective immunity elicited by HB vaccines, which is usually polyclonal in nature, may not be totally lost or severely affected in vivo by the alteration of only a single amino acid in the conformation of the a epitope.…”

“…[21][22][23][24][25][26][27] Also, such HBV mutants have been identified in chronic HBV carriers who acquired HBV infection naturally. [28][29][30][31] Because the a determinant of the HBV S protein is believed to contain a major neutralization epitope of HBV, it has been postulated that S gene mutants are generated by immune pressure and that they may spread among vaccinated individuals.…”

Clinical implications of mutations in the hepatitis B virus genome

“…This was first described in Italian children, born from HBsAg-positive mothers, who received a combination of active and passive immunoprophylaxis [40]. The same mutation has been described subsequently all over the world [41,42] not only in vaccine recipients but also in chronic HBV carriers [36,37]. Other relatively frequent vaccine escape mutants have been described that contain amino acid substitutions at the following positions: threonine or isoleucine → asparagine at position 126 [43] and lysine → glutamic acid at position 141 [44].…”

“…Other mutations able to interfere significantly with the antibody binding have been identified mainly in the Far East. For example, the presence of a short amino acid insertion between amino acids 121-124 results in false negativity for HBsAg [36][37][38].…”

Quasispecies and its impact on viral hepatitis

“…Variation of the "a" antigenic determinant has been associated with some cases of anti-HBV vaccine failure [reviewed in ]. Amino acid substitutions in the S protein are frequent among human carriers who are seropositive for anti-s antibodies (Yamamoto et al, 1994). The relevance of HBV s antigen mutants at the epidemiological level is suggested by an increase in the prevalence of s mutants following anti-HB vaccination of children (Hsu et al, 1999).…”