B Surface Proteins
Within the HBV genome, the region encoding the HBV surface proteins contains three in-frame start sites which share a common termination codon. Because of this, the various HBV surface proteins are all related to each other by a shared region known as the S-domain.
This protein is the smallest of the hepatitis B surface proteins, containing solely the S-domain. Historically, it also has been referred to as the Australia antigen (Au antigen). It is highly hydrophobic, containing four-transmembrane spanning regions. The HBsAg contains a high number of cysteines,14 all together, each of which is cross-linked to one another. It also may be glycosylated at Asp146. The two forms of this protein are commonly seen on gels run on HBsAg particles purified from carrier serum. This protein is the prime constituent of all hepatitis B particle forms. As such, this protein appears to be manufactured by the virus in high quantities. It also contains a highly antigenic epitope. Analysis of this epitope allows for the subtyping of HBV carriers.
Computer modelling implicates helices 3 and 4 as transmembrane spanning regions inserted postranslationally into the ER membrane. These two helices are thought to be the site of multimerization. This has been supported by observations which show truncated versions of the HBsAg missing in these helices. These helices are unable to form particles and remain in the ER.
Infected cells in the early stages produce this protein in the greatest quantities. The titre of the resulting non-infectious HBsAg particles found in a carrier's serum can be as high as 200ug/mL. Expression of the HBsAg appears to be inducible by stress in the endoplasmic reticulum typically due to the presence of high amount of LHBsAg.
Despite the high antigenicity and prevalence of these particles, the immune system appears basically oblivious to their presence. Studies, on T-lymphocyte-derived soluble factors in the maintenance of HBV infection, have shown that HBsAg of T-cell origin appears to suppress HBsAg-antibody production in other T-cells. Suppression is antigen specific for HBsAg. Immune suppression of antibodies against the various components of HBV favours persistence found in the chronic HBV carrier state.
The S promoter lies within the preS region. Mutations in this region result in lowered HBsAg production. Reduced production of the HBsAg appears to lead to intracellular retention of the virus. It also causes viral misassembly.
Subtypes of SHBsAg were originally defined by antibody recognition. Antigenic domains present on all known HBs isolates were classified as determinant a. The four other major subtypes are d or y and w or r. These two sets are paired and the members of each pair are mutually exclusive. Determinant d has a lysine at residue 122 while y has an arginine. Similarly, determinant w has a lysine at residue 160 while r has an arginine.
Recently, other determinants have been found which contain antigenic epitopes unrecognizable by antibodies against the above-mentioned subtypes. Because some antibodies are sub-type specific, it leads to the question: Does vaccination using HBs particles immunize a person against all HBV strains? The answer is "Yes", so far. However, in the more recent years, escape mutants have been found, showing a need for an improved vaccine or treatment.Middle Hepatitis B Surface Antigen (MHBsAg)
This intermediate or middle-sized HBV surface protein contains an additional 55 amino-acid domain known as Pre-S2. This domain is hydrophilic and appears to reside extracellularly. The Pre-S2 domain also contains an additional glycosylation site at Asp4. It appears that this site is always glycosylated, but the glycosylation site on the S-domain is only glycosylated at times, resulting in either a fully or partially glycosylated form of this protein.
Some have proposed that this protein is involved in HBV attachment and entry into the liver. However, in a study involving genetic analysis of HBV in patients with fulminant hepatitis, the pre-S2 start codon carried a double mutation, preventing expression of the corresponding protein. As such, it appears pre-S2 is not required for HBV infectivity nor viral particle morphogenesis. This likely excludes the middle HBsAg from being the HBV binding protein, though it may contribute to viral attachment as a secondary mechanism.
This protein is the largest of the HBV surface proteins, containing the Pre-S1 domain as well as the Pre-S2 and S domains. The Pre-S1 domain's sequence appears to be highly variable among infected patients, suggesting that this may be the HBV protein involved in liver attachment. The Pre-S1 domain contains no additional glycosylation sites, but contains a myristylation signal at its N-terminus, anchoring the N-terminus to the membrane.
There are two proposed different folding patterns for this protein: one found on the cell surface and in mature virions, the other found on the surface of the endoplasmic reticulum (ER). The predicted folding patterns are based on protease and antibody studies. In the related duck hepatitis B virus, the LHBsAg has also been shown to have dual topology. It appears that both the Pre-S1 and Pre-S2 domains remain cytoplasmic when the LHBsAg is in the ER. As such, the Pre-S2 domain remains unglycosylated whereas the Pre-S1 domains becomes myristylated. When, where, and how the PreS domains are translocated across the membrane are still under debate. However, a model has been proposed for the duck hepatitis B viral model. The model predicts that the PreS domains are translocated through an aqueous pore in the virus envelope. This pore is likely formed by the oligomerization of the transmembrane spanning regions in the S-domain
Overexpression of the LHBsAg alone results in ER retention of the protein. However, it was first suggested that ER retention was due to a cytosolic factor binding the LHBsAg as a transmembrane protein. However, more recent evidence shows formation of intracellular particles of LHBsAg in the lumen of the ER. Retention appears to be due to the binding of LHBsAg to calnexin.
This protein is believed by most to be the one responsible for mediating viral attachment onto its host cells. However, the receptor for HBV has not been isolated.
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