Structural insights into the binding of hepatitis B virus core peptide to HLA‐A2 alleles: Towards designing better vaccines

Abstract

Binding of specific antigenic peptides with human leukocyte antigen (HLA) molecules is a prerequisite for the initiation of T-cell responses and structural information about the peptide-HLA complex is essential for the detailed understanding of such interactions. HLA-A2 is the most prevalent HLA allele globally but aside from A*02:01 there is a significant lack of crystal structures, particularly for alleles that occur in high frequencies among Asian populations. Here, we report three HLA-A2 structures with the immunodominant hepatitis B core antigen 18-27 (HBcAg18-27) epitope, namely A*02:03, A*02:06, and A*02:07 at resolutions of 2.16, 1.70, and 1.75 Å respectively. This comparative analysis reveals that minor polymorphic residue changes between different HLA alleles can induce significant alterations in the major histocompatibility complex-peptide interface, and introduce conformational changes in the p3-p8 peptide region. Circular dichroism analysis demonstrated the HLA-A2-peptide complexes to have a hierarchy of thermostability and binding affinity in the order of A*02:06>A*02:07>A*02:01>A*02:03. Our findings provide structural insights into the varied HLA-A2 allele binding of the hepatitis B core antigen 18-27 epitope and the data suggest that chemical modifications of the peptide side chains could be a promising strategy to modulate and improve HLA-A2-peptide binding affinity for vaccine design.Key words: Antigen . Hepatitis B virus . Human leukocyte antigen . Immunogenicity . Vaccine Supporting Information available online IntroductionChronic hepatitis B infection is accompanied by many follow-on complications such as liver cirrhosis and hepatocellular carcinoma (HCC), and hence the prevention and treatment of hepatitis B virus (HBV) infection is an important target for public health strategies. Specific HBV epitopes are known to elicit efficient T-cell-mediated antiviral responses in subjects who resolve infection, whereas the lack of an antiviral CD8 1 T-cell response is associated with chronically infected patients [1]. The HBV core 18-27 peptide (HBcAg18-27), which is one of the most wellcharacterized markers of protection against HBV, was originally described as a human leukocyte antigen (HLA)-A2.1-restricted CTL (cytotoxic T lymphocyte) epitope and was detected in more than 90% of HLA-A2.1 patients who resolved acute HBV infection [2,3]. This and other therapeutic peptides have been used to shift cellular immunity toward viral elimination and the studies of HLA-class I-restricted CD8 1 T-cell responses to HBV were mainly conducted using peptides that bind specifically to HLA-A Ã 02:01 molecules [4,5]. Interestingly, a recent study showed that the presence of valine at the C-terminal of HBcAg18-27 is associated with severe liver inflammation in Chinese patients with chronic Results Crystal dataThe crystal structures of A Ã 02:03, A Ã 02:06, and A Ã 02:07 were determined at resolutions of 2.16, 1.70, and 1.75 Å respectively. The HLA-peptide structures were refined to a reasonable agreement between t...

Structural basis for the differential classification of HLA-A*6802 and HLA-A*6801 into the A2 and A3 supertypes

“…These two groups can present the peptides with similar motif at P2 and Pc positions but in subtle different conformations. A recent structural study elucidated the peptide presentation features of four HLA-A*0201-like molecules: HLA-A*0201, HLA-A*0203, HLA-A*0206, and HLA-A*0207 (Liu et al, 2011a). Herein our structures of HLA-A*6802 provide the insights into the peptide presentation of the HLA-A*6802like group.…”

“…A previous study indicates that the peptides presented by the HLA alleles from the A2 supertype prefer aromatic amino acids such as Tyr as secondary anchors at the P3 position (Sidney et al, 2001). Herein, base on the structure of HLA-A*6802/TRP2-180, a different binding mode for the P3 Tyr anchor of HLA-A*6802 is displayed when compared to other A2 supertype members (Liu et al, 2011a). In accord with the unusual P3 Tyr anchoring, the middle portion of the peptide binding groove of HLA-A*6802/TRP2-180 is wider than HLA-A*0201 (Fig.…”

Conserved epitopes dominate cross‐CD8+T‐cell responses against influenza A H1N1 virus among Asian populations

“…The responses against GL9 were examined to diverse extents among different individuals. Several individuals have few or even undetectable GL9‐specific T cells in the PBMCs that may be attributed to the different cross‐recognition of GL9 among different alleles from HLA‐A2 supertype . However, the GL9‐specific T cells statistically occupied the majority of the influenza virus‐specific T cells (tested by the Conserved‐pool) among different HLA‐A2 + individuals.…”

Identification of HLA-A*0201-restricted CD8+ T-cell epitope C64–72 from hepatitis B virus core protein

“…However, these responses are compromised or below detection levels in patients with chronic infection [13,42]. Up to date, to our knowledge, 5 HLA-A2 restricted HBcAg-specific CTL epitopes have been reported [32][33][34][43][44][45][46] and among these, immunodominant hepatitis B core antigen 18-27 (HBcAg 18-27 ) epitope has been applied widely [47][48][49][50]. In this study we identify a new HLA-A*0201 restricted HBV core antigen-specific CTL epitope (C 64-72 , ELM-TLATWV).…”