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Variability and conservation in hepatitis B virus core protein.

Chain BM, Myers R - BMC Microbiol. (2005)

Bottom Line: Polymorphisms were found at 44 out of 185 amino acid positions analysed and were clustered predominantly in those parts of HBVc forming the outer surface and spike on intact capsid.The structural requirements of capsid assembly are likely to play a major role in limiting diversity.The phylogenetic analysis further suggests that immunological selection does not play a major role in driving HBVc diversity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Immunology and Molecular Pathology, University College London, W1T 4JF UK. b.chain@ucl.ac.uk

ABSTRACT

Background: Hepatitis B core protein (HBVc) has been extensively studied from both a structural and immunological point of view, but the evolutionary forces driving sequence variation within core are incompletely understood.

Results: In this study, the observed variation in HBVc protein sequence has been examined in a collection of a large number of HBVc protein sequences from public sequence repositories. An alignment of several hundred sequences was carried out, and used to analyse the distribution of polymorphisms along the HBVc. Polymorphisms were found at 44 out of 185 amino acid positions analysed and were clustered predominantly in those parts of HBVc forming the outer surface and spike on intact capsid. The relationship between HBVc diversity and HBV genotype was examined. The position of variable amino acids along the sequence was examined in terms of the structural constraints of capsid and envelope assembly, and also in terms of immunological recognition by T and B cells.

Conclusion: Over three quarters of amino acids within the HBVc sequence are non-polymorphic, and variation is focused to a few amino acids. Phylogenetic analysis suggests that core protein specific forces constrain its diversity within the context of overall HBV genome evolution. As a consequence, core protein is not a reliable predictor of virus genotype. The structural requirements of capsid assembly are likely to play a major role in limiting diversity. The phylogenetic analysis further suggests that immunological selection does not play a major role in driving HBVc diversity.

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Variation with CD4 and antibody epitopes of HBVc. a) Two of the best defined CD4 epitopes within HBVc (taken from [31,32]) are shown together with alternative amino acids found at each position. The position of the epitope 50#150;69 is shown in the context of the HBVc three dimensional structure above(in green). The rest of the colour coding is as shown in fig 6. Epitope 147#150;156 is not shown since this region of HBVc was excluded in the crystallographic study. b) The best defined antibody epitopes (taken from [33]) are shown (in green) in the context of the HBVc three dimensional structure above. The rest of the colour coding is as shown in fig 6.
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Figure 9: Variation with CD4 and antibody epitopes of HBVc. a) Two of the best defined CD4 epitopes within HBVc (taken from [31,32]) are shown together with alternative amino acids found at each position. The position of the epitope 50#150;69 is shown in the context of the HBVc three dimensional structure above(in green). The rest of the colour coding is as shown in fig 6. Epitope 147#150;156 is not shown since this region of HBVc was excluded in the crystallographic study. b) The best defined antibody epitopes (taken from [33]) are shown (in green) in the context of the HBVc three dimensional structure above. The rest of the colour coding is as shown in fig 6.

Mentions: The evidence implicating CD4 T cells in HBV control remains much less clear. Furthermore, although regions containing CD4 epitopes have been described, many of the epitopes are not very well characterised. One putative "immunodominant" CD4 T cell epitope (amino acids 50-69) does contain a number of variable amino acids (fig 9a), and indeed changes in its sequence have been related directly to changes in T cell response in vivo [31]. A second epitope (core region 147-156) identified as a major target in HLADR13 individuals has also been examined in some detail [32]. Interestingly this epitope also shows considerable variation (fig 9a) including a mutation at position 151 shown to be essential for T cell recognition. The epitope also spans the region of a two amino acid insertion which is found exclusively in viruses of genotype A. Further detailed mapping of CD4 T cell recognition sites, in relation to natural sequence variation would be seem to be an area of great interest.


Variability and conservation in hepatitis B virus core protein.

Chain BM, Myers R - BMC Microbiol. (2005)

Variation with CD4 and antibody epitopes of HBVc. a) Two of the best defined CD4 epitopes within HBVc (taken from [31,32]) are shown together with alternative amino acids found at each position. The position of the epitope 50#150;69 is shown in the context of the HBVc three dimensional structure above(in green). The rest of the colour coding is as shown in fig 6. Epitope 147#150;156 is not shown since this region of HBVc was excluded in the crystallographic study. b) The best defined antibody epitopes (taken from [33]) are shown (in green) in the context of the HBVc three dimensional structure above. The rest of the colour coding is as shown in fig 6.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1173110&req=5

Figure 9: Variation with CD4 and antibody epitopes of HBVc. a) Two of the best defined CD4 epitopes within HBVc (taken from [31,32]) are shown together with alternative amino acids found at each position. The position of the epitope 50#150;69 is shown in the context of the HBVc three dimensional structure above(in green). The rest of the colour coding is as shown in fig 6. Epitope 147#150;156 is not shown since this region of HBVc was excluded in the crystallographic study. b) The best defined antibody epitopes (taken from [33]) are shown (in green) in the context of the HBVc three dimensional structure above. The rest of the colour coding is as shown in fig 6.
Mentions: The evidence implicating CD4 T cells in HBV control remains much less clear. Furthermore, although regions containing CD4 epitopes have been described, many of the epitopes are not very well characterised. One putative "immunodominant" CD4 T cell epitope (amino acids 50-69) does contain a number of variable amino acids (fig 9a), and indeed changes in its sequence have been related directly to changes in T cell response in vivo [31]. A second epitope (core region 147-156) identified as a major target in HLADR13 individuals has also been examined in some detail [32]. Interestingly this epitope also shows considerable variation (fig 9a) including a mutation at position 151 shown to be essential for T cell recognition. The epitope also spans the region of a two amino acid insertion which is found exclusively in viruses of genotype A. Further detailed mapping of CD4 T cell recognition sites, in relation to natural sequence variation would be seem to be an area of great interest.

Bottom Line: Polymorphisms were found at 44 out of 185 amino acid positions analysed and were clustered predominantly in those parts of HBVc forming the outer surface and spike on intact capsid.The structural requirements of capsid assembly are likely to play a major role in limiting diversity.The phylogenetic analysis further suggests that immunological selection does not play a major role in driving HBVc diversity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Immunology and Molecular Pathology, University College London, W1T 4JF UK. b.chain@ucl.ac.uk

ABSTRACT

Background: Hepatitis B core protein (HBVc) has been extensively studied from both a structural and immunological point of view, but the evolutionary forces driving sequence variation within core are incompletely understood.

Results: In this study, the observed variation in HBVc protein sequence has been examined in a collection of a large number of HBVc protein sequences from public sequence repositories. An alignment of several hundred sequences was carried out, and used to analyse the distribution of polymorphisms along the HBVc. Polymorphisms were found at 44 out of 185 amino acid positions analysed and were clustered predominantly in those parts of HBVc forming the outer surface and spike on intact capsid. The relationship between HBVc diversity and HBV genotype was examined. The position of variable amino acids along the sequence was examined in terms of the structural constraints of capsid and envelope assembly, and also in terms of immunological recognition by T and B cells.

Conclusion: Over three quarters of amino acids within the HBVc sequence are non-polymorphic, and variation is focused to a few amino acids. Phylogenetic analysis suggests that core protein specific forces constrain its diversity within the context of overall HBV genome evolution. As a consequence, core protein is not a reliable predictor of virus genotype. The structural requirements of capsid assembly are likely to play a major role in limiting diversity. The phylogenetic analysis further suggests that immunological selection does not play a major role in driving HBVc diversity.

Show MeSH
Related in: MedlinePlus