Reduced hepatitis B virus surface antigen-specific Th1 helper cell frequency of chronic HBV carriers is associated with a failure to produce antigen-specific antibodies in the trimera mouse

In chronic hepatitis B virus (HBV) infection weak antiviral immune response s are associated with viral persistence. We studied possible immune deficit s underlying the lack of serum antibodies of such patients against the HBV surface antigen (HBsAg) in a novel human/mouse chimeric model. A hepatitis B surface antigen (HBs) vaccination of Balb/c mice engrafted with periphera l blood mononuclear cells (PBMC) of naturally HBV-immunized donors induced high frequencies of human HBsAg-specific B and T helper 1 (Th1) cells. Thes e responses were associated with high serum anti-HBs antibody levels of the subclasses immunoglobulin G1 (IgG1) and IgG2 that are driven by interleuki n-2 (IL-2) and interferon-gamma (IFN-gamma). In contrast, PBMC of chronic H BV carriers transplanted into the chimera failed to produce anti-HBs antibo dies after vaccination with HBsAg and exhibited a deficit of antigen-specif ic Th1 cells, A possible influence of HBsAg or viremia was excluded by the lack of viral replication in such chimera. The observed T-cell defect was s pecific for HBsAg, as the B- and T-cell responses to tetanus toroid (TT) we re fully retained, Thus, our study shows that viral persistence in chronic HBV carriers is associated with an HBsAg-specific Th1 cell defect, which li kely is responsible for the insufficient neutralizing anti-HBs-antibody res ponse and is not reversed by HBs vaccination. Alternative approaches to ind uce HBs-specific Th1 cell responses might represent a future therapeutic op tion.