Hepatitis B Virus Core Antigen Binds and Activates Naive Human B Cells In Vivo: Studies with a Human PBL-NOD/SCID Mouse Model

The hepatitis B virus (HBV) core (HBc) antigen (HBcAg) is a highly immunogenic subviral particle. Studies with mice have shown that HBcAg can bind and activate B cells in a T-cell-independent fashion. By using a human peripheral blood leukocyte (hu-PBL)-Nod/LtSz-Prkdc(scid)/Prkdc(scid) (NOD/SCID) mouse model, we show here that HBcAg also activates human B cells in vivo in a T-cell-independent way. HBcAg was capable of inducing the secretion of HBcAg-binding human immunoglobulin M (IgM) in naive human B cells derived from adult human and neonatal (cord blood) donors when these hu-PBL were transferred directly into the spleens of optimally conditioned NOD/SCID mice. No such responses were found in chimeric mice that were given hu-PBL plus HBV e antigen or hu-PBL plus phosphate-buffered saline. In addition, HBcAg activated purified human B cells to produce anti-HBc IgM in the chimeric mice, thus providing evidence that HBcAg behaves as a T-cell-independent antigen in humans. However, HBcAg-activated hu-PBL from naive donors were unable to switch from IgM to IgG production, even after a booster dose of HBcAg. Production of HBcAg-specific IgG could only be induced when hu-PBL from subjects who had recovered from or had an ongoing chronic HBV infection were transferred into NOD/SCID mice. Our data suggest that humans also have a population of naive B cells that can bind HBcAg and is subsequently activated to produce HBcAg-binding IgM.