Reduced Antigenicity of the Hepatitis B Virus HBsAg Protein Arising as a Consequence of Sequence Changes in the Overlapping Polymerase Gene That Are Selected by Lamivudine Therapy

Abstract

The prevalence of hepatitis B virus vaccine escape mutants has increased as a consequence of the introduction of global vaccination programs. Furthermore and as a consequence of the organization of the genome of hepatitis B virus (HBV) into overlapping reading frames, the selection of polymerase mutants during long-term lamivudine therapy can select viruses with changes in the overlapping S gene coding for the hepatitis B small antigen (HBsAg). We have investigated the role of lamivudine in selecting HBV mutants with antigenically altered HBsAg protein using pooled human vaccine sera in enzyme immunosorbent assays and radioimmunoassays. HBsAg proteins containing the vaccine escape mutations G145R and D144E/G145R demonstrated markedly reduced binding to anti-HBs antibody. HBsAg mutants including E164D, W196S, I195M, M198I, and E164D/I195M (corresponding to the polymerase protein changes of V519L, M550I, L526M/M550V V553I, and V519L/L526M/M550V) selected during lamivudine treatment also demonstrated reduced binding to anti-HBs antibody. These findings raise the possibility of lamivudine-resistant mutants arising that possess antigenically distinct HBsAg proteins.

Patterns of hepatitis B virus infection in Brazilian human immunodeficiency virus infected patients: high prevalence of occult infection and low frequency of lamivudine resistant mutations

“…The triple mutation V519L/L526M/ M550V causes the concomitant amino acid substitutions E164D and I195M in the S protein. It has been shown recently that this triple mutant has a reduced affinity to anti-HBs antibodies, similarly to what happens with the well-known hepatitis B vaccine escape mutant G145R (Torresi et al 2002, Cooley et al 2003.…”

“…In addition, one sample displayed a third, previously described (Torresi et al 2002, Cooley et al 2003 lamivudine resistance mutation, namely V519L. The triple mutation V519L/L526M/ M550V causes the concomitant amino acid substitutions E164D and I195M in the S protein.…”

“…The deduced polymerase amino acid sequences showed that, despite the long period of lamivudine administration, only three isolates (patients 3, 4, and 12) showed the double L526M and M550V resistance mutation (Table III). One of them (patient 12) showed an additional mutation (V519L), which has also been related to lamivudine resistance (Torresi et al 2002). Isolates 3, 4, and 12 belonged to genotype A, subgroup Aa.…”

Global control of hepatitis B virus: does treatment-induced antigenic change affect immunization?

“…This process results in new, closely-related viral species; as a result, at any given time in a particular host the viral population consists of a swarm of similar but discrete viruses. 6,7 Vaccine escape mutants up to 95% of recipients. 8 The envelope gene of HBV produces proteins of three different lengths: two larger proteins, preS1 and preS2, as well as the smaller S protein.…”

Hepatitis B Virus (HBV) Variants in Hemodialysis Patients

“…The triple lamivudine resistance mutation causes the concomitant amino acid substitutions E164D and I195M in the HBsAg as a result of the overlapping reading frames of the envelope and polymerase genes (Locarnini, 1998). It has been shown that both E164D and I195M substitutions reduce in vitro affinity of HBsAg to anti-HBs antibodies, similar to the HBV vaccine escape mutant G145R (Torresi et al, 2002). The HBsAg Y100C substitution is also frequently found among occult HBV infection carriers.…”