Identification and characterization of HBV core CTL epitopes in Indonesian samples

Abstract

Hepatitis B virus (HBV) is a non-cytopathic virus that causes liver disease with variable duration and severity. During infection, host immune response is responsible for both liver damage and viral clearance. The adaptive immune response, particularly virus-specific cytotoxic T lymphocyte (CTL) response, has been shown to play a major role in HBV infection immunopathogenesis by destroying the infected hepatocytes or eliminating HBV in a non-cytolytic manner. From virus-host interaction perspective, HBV core antigen (HBcAg) has been of interest because it is a major immunological target of CTL. Many human leucocyte antigen (HLA)-restricted HBcAg T cell epitopes have been reported which might be different due to the diverse distribution ethnic-specific HLA in distinct geographical regions. Therefore, it is important to identify and characterize HBcAg CTL epitopes in area with high HBV endemic and high population diversity like Indonesia. To support HBcAg as a promising protein to develop CTL epitope-based vaccine, HBcAg sequences of samples from individuals in Indonesia were analyzed. It was found that the sequences were conserved, and amino acid substitutions observed did not reflect the influence of human leucocyte antigen (HLA) types on the HBcAg variability. To develop such a vaccine, the first thing to do is to determine the peptide(s) that must be immunogenic and can interact with HLA class I proteins of Indonesian populations. Using immunoinformatic approaches, 20 HBcAg CTL epitopes (14 nonamers and 6 decamers) against HLA alleles in Javanese, Sundanese-Javanese, and T ernatean populations were identified. These 20 CTL epitopes were also characterized for sequence variation and conservation in 125 HBcAg of Indonesian isolates. Variations of HBcAg CTL epitope were detected, but one variant was found to be predominant in each epitope. By immunoinformatic analysis, different binding affinity was observed for each variant. The difference was found to depend on the location and type of amino acid in related epitope that affect its interaction with HLA binding grooves. The present study describes the use of immunoinformatic approaches as a pilot study to identify HBcAg-CTL epitopes of Indonesian isolates and analyze their conservation and variability. Of 20 CTL epitopes, HBcAg 18-27 was found the best CTL epitope for the Indonesian populations represented by the Javanese, Sundanese-Javanese, and Ternatean. Among the discovered epitope variants, residue FLPSDFFPSI was identified as the best candidate to develop peptide-based vaccine due to its predominance among all isolates studied. This study will be beneficial for developing an approach for successful viral control in hepatitis B patients.