Methods for the study of pre-S proteins of hepatitis B virus and their antibodies: pathogenetic and clinical implications

The envelope gene of hepatitis B virus (HBV) consists of a large open reading frame which codes 3 different polypeptides by the variable use of 3 contiguous regions: the pre-S1, pre-S2 and S regions. The protein coded by the entire sequence (L protein) is identified by its unique pre-S1 epitopes and has a role in virus assembly and secretion. Pre-S1 antigens are expressed preferentially on virions and are less abundant, but present, on subviral particles. The pre-S2 sequence contains a species-specific receptor for polyalbumin, which has been implicated in virus binding to hepatocytes. Methods have been recently developed to measure pre-S1 and pre-S2 levels in serum and available data indicate that these assays may be useful in prognostic assessment of acute hepatitis B and to measure virus replication in chronic infection, although further studies are certainly needed to define specificity and sensitivity compared to conventional HBV markers. Both pre-S1 and pre-S2 are highly immunogenic and elicit anti-pre-S antibodies. Methods for detection of anti-pre-S in human sera have proved difficult to be developed due to unspecific reaction of serum components with pre-S sequences and epitope variability of the immune response in humans. Anti-pre-S2 seems a marker of recovery from acute infection, while evidence of its involvement in liver damage is weak. Both anti-pre-S2 and anti-pre-S1, but we have limited information on the latter, may be involved in virus neutralization. These issues are particularly relevant for future HB vaccine development, as it is proposed that inclusion of strategic pre-S sequences could increase efficacy.