Emergence of hepatitis B virus S gene mutant in a liver transplant recipient

Abstract

Immunological and genomic analysis of the "a" determinant was carried out in seven patients with concurrent HBsAg and anti-HBs, four of whom were immunized against hepatitis B virus at liver transplant, two with histologically characterized chronic hepatitis B virus infection, and one HBsAg healthy carrier. The immune reactivity of the HBsAg "a" determinant was evaluated by binding to specific monoclonal antibodies, and the corresponding genomic sequence was studied by differential hybridization in microtiter plates and nucleotide sequence analysis. A double mutation generating an amino acid change (glycine to lysine) at residue 145, able to impair recognition by monoclonal antibodies, was observed in the post-transplant serum from one patient. No significant alteration of the "a" determinant sequence or reactivity was detected in the other patients. Amino acid residue 145 appears therefore to be critical for the recognition by anti-HBs antibodies. A previously undescribed glycine to lysine substitution at this level interferes with the immune reactivity of the "a" determinant.

Hepatitis B virus with antigenically altered hepatitis B surface antigen is selected by high-dose hepatitis B immune globulin after liver transplantation

“…40 sD144G and sG145K were recently described as a cause of reinfection after liver transplantation in single patients. 19,21,41 Sequencing of clones showed conclusively that, once an aa s144 or s145 variant had emerged, it predominated over pre-OLT standard sequence strains in all cases.…”

“…Recently, four patients were reported who experienced graft infection after liver transplatation with sG145R or sG145K mutant HBV despite HBIG. [19][20][21] A 226-aa sequence of the small surface (s)-protein is shared by all three envelope proteins of HBV. S-protein is secreted from HBV-infected cells in the form of 22-nm spherical subviral HBsAg particles.…”

Predictions of the emergence of vaccine-resistant hepatitis B in The Gambia using a mathematical model

“…Hepatitis B virus (HBV) variants have been reported to arise in immunized individuals in three situations : (i) after liver transplantation, despite treatment with monoclonal antibodies against surface antigen (antiHBs) and hyper-immunoglobulin (HBIG) treatment [1][2][3], (ii) neonatal infections, despite HBIG and\or vaccination in the UK [4], Italy [5], Singapore [6], Indonesia [7] and Japan [8], and (iii) horizontal infections in young children despite vaccination in The Gambia [9]. The 22 nm subviral surface antigen peptides (HBsAg) used in the current vaccines (both plasma derived and recombinant) produce a narrower immune response than immunity following infection.…”

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

“…There is evidence for the emergence of hepatitis B virus (HBV) mutants with amino acid substitutions in the a determinant of the surface (S) protein in individuals who received immunoprophylaxis against HBV either at birth [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] or during liver transplantation. [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.…”