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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.

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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 within CD8 T cell epitopes of HBVc. Five of the best defined class I T cell epitopes from HBVc (for references see text) are shown together with alternative amino acids found at each position. The position of the epitopes (green) within the HBVc three dimensional structure is shown in the right hand panel. The rest of the colour coding is as shown in fig 6.
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Figure 8: Variation within CD8 T cell epitopes of HBVc. Five of the best defined class I T cell epitopes from HBVc (for references see text) are shown together with alternative amino acids found at each position. The position of the epitopes (green) within the HBVc three dimensional structure is shown in the right hand panel. The rest of the colour coding is as shown in fig 6.

Mentions: Pressure by the host immune system is one obvious candidate driving variation in the protein sequence of HBVc. CD8 cytotoxic cells are believed to play a key role in controlling virus replication during HBV infection [24,25]. Several CD8 T cell epitopes have been characterised in detail (e.g. [26-28]) by the use of T cell clones and lines or by elution from HLA [29]. Some of the sequences are shown in fig 7, together with the known variant sequences in the dataset analysed in this study. Although several of the epitopes lie within the more conserved inner region of the capsid, two of the epitopes show substantial polymorphism (fig 8). Interestingly, a previous paper did not find any evidence for emergence of mutations within the major CD8 epitopes during chronic HBV infection [30].


Variability and conservation in hepatitis B virus core protein.

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

Variation within CD8 T cell epitopes of HBVc. Five of the best defined class I T cell epitopes from HBVc (for references see text) are shown together with alternative amino acids found at each position. The position of the epitopes (green) within the HBVc three dimensional structure is shown in the right hand panel. The rest of the colour coding is as shown in fig 6.
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Related In: Results  -  Collection

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

Figure 8: Variation within CD8 T cell epitopes of HBVc. Five of the best defined class I T cell epitopes from HBVc (for references see text) are shown together with alternative amino acids found at each position. The position of the epitopes (green) within the HBVc three dimensional structure is shown in the right hand panel. The rest of the colour coding is as shown in fig 6.
Mentions: Pressure by the host immune system is one obvious candidate driving variation in the protein sequence of HBVc. CD8 cytotoxic cells are believed to play a key role in controlling virus replication during HBV infection [24,25]. Several CD8 T cell epitopes have been characterised in detail (e.g. [26-28]) by the use of T cell clones and lines or by elution from HLA [29]. Some of the sequences are shown in fig 7, together with the known variant sequences in the dataset analysed in this study. Although several of the epitopes lie within the more conserved inner region of the capsid, two of the epitopes show substantial polymorphism (fig 8). Interestingly, a previous paper did not find any evidence for emergence of mutations within the major CD8 epitopes during chronic HBV infection [30].

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