Endocytosis of Hepatitis B Immune Globulin into Hepatocytes Inhibits the Secretion of Hepatitis B Virus Surface Antigen and Virions

Abstract

Hepatitis B immunoglobulin is used for prophylaxis against hepatitis B virus (HBV) and is thought to act by neutralization of virions and hepatitis B virus surface antigen (HBsAgHepatitis B immunoglobulin (HBIG) is used clinically as passive immunoprophylaxis for accidental exposure to hepatitis B virus (HBV) and long term to prevent HBV recurrence in the graft after liver transplantation (24). It contains high-titer antibodies against HBV surface antigen (HBsAg), which is the major component of the outer envelope of the 42-nm-diameter hepatitis B virion, as well as the 22-nm-diameter subviral particles. The therapeutic effect of HBIG is believed to be due to high-affinity binding with HBs-containing particles and neutralization of HBV in the circulation.Despite HBIG prophylaxis, HBV infection recurs in 30% of patients who receive transplants for HBsAg-positive cirrhosis (24). The failure of immunoprophylaxis is due either to a high HBV load and inadequate neutralization by HBIG or to the emergence of antibody-induced escape HBV mutants (3, 6, 25). These mutant HBV strains contain amino acid substitutions within the conserved a-determinant (a group-reactive region between amino acids 124 and 149 of HBsAg), which abrogate the binding affinity of anti-HBs (4, 5, 22, 27). The most frequent mutation occurs at codon 145 of the surface open reading frame, leading to a glycine (G)-to-arginine (R) substitution-G145R-which has been shown to emerge both in liver transplant patients receiving HBIG prophylaxis and in HBV vaccine recipients (2,6,22). The mechanism for the emergence of HBsAg mutations that escape antibody recognition has not been defined.Earlier studies have demonstrated the presence of membrane-bound and/or nuclear localization of immunoglobulin G (IgG) in hepatocytes of patients with chronic HBV infection, who express HBV core antigen or hepatitis delta virus antigen in the liver (17,19,23). Recently, a novel Fc receptor for IgG (FcRn) which mediates the transcytosis of IgG from serum to bile and protects the internalized IgG from catabolism has been identified on the plasma membranes of adult rat hepatocytes (1, 9). FcRn is a heterodimer of ␤ 2 -microglobulin light chain and a major histocompatibility complex class I-like heavy chain that binds IgG via Fc residues in a pH-dependent manner. IgG binding to FcRn is followed by endocytosis of the complex in the acidic endosome environment, trafficking through cellular conduits to bypass lysosomal activities and finally releasing IgG in the extracellular fluids (7). Whether hepatitis B immunoglobulin enters HBV-infected hepatocytes and whether an interaction with HBsAg occurs within cells, in addition to the interaction in serum, have not been investigated.In the present study, we investigated the hypothesis that HBIG is able to bind to hepatocytes and affect the secretion of HBsAg and HBV virions from the cells. For this purpose, we used a panel of human hepatocyte-derived cell lines cultured together with monoclonal and polyclonal HBs-specific antibodies. The...

Fcγ receptor-like hepatitis C virus core protein binds differentially to IgG of discordant Fc (GM) genotypes

“…Studies by Schilling et al (2003) suggest that FcRn mediates the cellular uptake of neutralizing IgG antibodies to the hepatitis B virus in hepatocytes and interferes with the secretion of the virions from the cells. Similar mechanisms may be applicable to the HCV as well.…”

A bispecific antibody against two different epitopes on hepatitis B surface antigen has potent hepatitis B virus neutralizing activity

“…15,17 Moreover, the combination of two anti-HBsAg antibodies showed a greater HBsAg retention within hepatocyte-derived cells than did either antibody alone. Here, we investigated whether the anti-HBsAg bispecific antibody C4D2-BsAb could be internalized in hepatocytes and interfere with secretion of HBsAg and virions from the infected-HBV cells.…”

“…We used PLC/PRF/5 cells, which provide the stable production of HBsAg. 17 PLC/PRF/5 cells were treated with C4G4, D2H2, C4G4 plus D2H2, C4D2-BsAb, and cIgG, respectively. After the first 24 h, the cells were washed and fresh medium was added.…”

Role of nucleoside/nucleotide analogues and low-dose hepatitis B immune globulin in prophylaxis of hepatitis B recurrence among cadaveric liver transplant recipients

“…The prophylactic use of HBIG alone resulted in 1-and 5-year post-LT survival rates as high as 85% and 75%, respectively; less than 5% graft reinfections was also observed (8,9). HBIG use as prophylaxis was based on the hypothesis that antibodies to HBsAg would bind and neutralize the circulating virions and reduce HBsAg secretion, thereby preventing graft infection (10). The combined use of HBIG and AV now has become the standard of care.…”