PreS antigen expression and anti-preS response in hepatitis B virus infections: relationship to serum HBV-DNA, intrahepatic HBcAg, liver damage and specific T-cell response

Abstract

The diagnostic value of preS antigens and anti-preS antibodies during Hepatitis B virus (HBV) infections have not yet been clearly elucidated. Therefore, the objectives of this study were: 1) to better understand the clinical significance of the expression of both preS1 and preS2 antigens (preS1Ag and preS2Ag) in the serum of chronic HBsAg carriers, and 2) to define the respective role of antibody responses to HBs-, preS2- and preS1-specific determinants in the course of acute hepatitis B (AH-B) infections with different outcomes. Our data showed that the serum preS1Ag/HBsAg ratio correlated well with the level of viral replication (serum HBV-DNA as monitored by PCR assay and liver HBcAg), especially in anti-HBe positive chronic carriers. The complete eradication of virions required a persistent antibody response to conformation-dependent HBs-epitopes, temporally associated with a vigorous T cell response to nucleocapsid antigens. Recovery from hepatitis B can be achieved when there is no early antibody response to preS2- and preS1-proteins, which was found to be transient, concomitant with a flare-up of the liver disease, and preceding anti-HBs production. Information on the patterns of preS antigens and their antibodies remained clouded because of the varying specificities and sensitivities of research methods used in studies to date. We have, therefore, developed original Polyclonal-Monoclonal RadioImmunoAssays (PAb-MAb RIAs) by using monoclonal antibodies (MAbs) having previously well-defined specificities. We could thus detect and quantify simultaneously the three distinct antigenicities of the HBV envelope, HBsAg, preS2Ag and preS1Ag, with the same sensitivity. In this way, the preS1Ag/HBsAg and preS2Ag/HBsAg ratios can be calculated to estimate the serum expression of both preS1Ag and preS2Ag in relation to total HBsAg activity during different stages of chronic HBV infection. For optimal management of the state of HBV replication in chronic viral infection, the detection of HBV-DNA in serum was monitored by the Polymerase Chain Reaction (PCR) assay. We extended our work by investigating the clinical significance of antibody response to preS-specific determinants in patients with AH-B showing different outcomes in both natural course or response to alpha-interferon therapy. In a first attempt, we chose to use the Western Immuno-Blotting Assay (WIBA) to obtain a qualitative assessment of the nature of preS antibody responses. Finally, the cell-mediated immune response to HBV antigens was also studied in several patients with self-limited AH-B leading to a relevant finding which may help to clarify the mechanisms responsible for complete clearance of HBV.