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The hepatitis B surface antigen (HBsAg) is a multifunctional glycoprotein composed of large (LHB), middle (MHB), and small (SHB) subunits. HBsAg isoforms have numerous biological functions during HBV infection—from initial and specific viral attachment to the hepatocytes to initiating chronic infection with their immunomodulatory properties. The genetic variability of HBsAg isoforms may play a role in several HBV-related liver phases and clinical manifestations, from occult hepatitis and viral reactivation upon immunosuppression to fulminant hepatitis and hepatocellular carcinoma (HCC). Their immunogenic properties make them a major target for developing HBV vaccines, and in recent years they have been recognised as valuable targets for new therapeutic approaches. Initial research has already shown promising results in utilising HBsAg isoforms instead of quantitative HBsAg for correctly evaluating chronic infection phases and predicting functional cures. The ratio between surface components was shown to indicate specific outcomes of HBV and HDV infections. Thus, besides traditional HBsAg detection and quantitation, HBsAg isoform quantitation can become a useful non-invasive biomarker for assessing chronically infected patients. This review summarises the current knowledge of HBsAg isoforms, their potential usefulness and aspects deserving further research.

Background and aims: CREB (cAMP response element binding protein) transcription factors are key regulators of homeostatic functions in the liver, and CRE binding is increased in hepatic inflammation. During chronic hepatitis B virus (HBV) infection, mutations or deletions in the pre-S region are frequently observed. These mutations can affect the pre-S2/S promoter controlling HBV envelope protein expression (hepatitis B surface antigen (HBsAg)) and have been associated with worsened clinical outcome. We aimed to test if CREB activation impacts on HBsAg expression. Methods: The effect of the CREB inducer protein kinase A (PKA) was tested by coexpression with HBV wild-type vector in vitro. Luciferase reporter gene constructs were cloned to identify novel regulatory regions for the HBV pre-S2/S promoter. Electrophoretic mobility shift assay (EMSA) gelshift and supershift experiments were conducted to confirm DNA transcription factor binding. Results: Coexpression of HBV and PKA resulted in HBV-S mRNA induction and enhanced small envelope protein expression. We identified a CREB binding motif in the transcribed part of the pre-S2 region, contributing to basal S promoter activity via binding of activating transcription factor 2 (ATF2). A second CREB motif closely linked to the S-ATG showed a similar binding pattern involving ATF2 and CREB1, without appearing essential for basal promoter activity. Moreover, a sequence in the pre-S2 region is responsible for further transcriptional induction via CREB activators such as PKA and forskolin. EMSA experiments indicate that CREB1 and ATF4 are involved in complex formation conferring PKA dependent promoter activation. Conclusions: Our data suggest a novel mechanism by which HBV may utilise CREB/PKA signal transduction pathways of hepatocytes to enhance its HBsAg expression during homeostasis and hepatic inflammation.