Associations between HLA Class I Alleles and Escape Mutations in the Hepatitis B Virus Core Gene in New Zealand-Resident Tongans

Abstract

The full repertoire of hepatitis B virus (HBV) peptides that bind to the common HLA class I molecules found in areas with a high prevalence of chronic HBV infection has not been determined. This information may be useful for designing immunotherapies for chronic hepatitis B. We identified amino acid residues under positive selection pressure in the HBV core gene by phylogenetic analysis of cloned DNA sequences obtained from HBV DNA extracted from the sera of Tongan subjects with inactive, HBeAg-negative chronic HBV infections. The repertoires of positively selected sites in groups of subjects who were homozygous for either HLA-B*4001 (n ‫؍‬ 10) or HLA-B*5602 (n ‫؍‬ 7) were compared. We identified 13 amino acid sites under positive selection pressure. A significant association between an HLA class I allele and the presence of nonsynonymous mutations was found at five of these sites. HLA-B*4001 was associated with mutations at E77 (P ‫؍‬ 0.05) and E113 (P ‫؍‬ 0.002), and HLA-B*5602 was associated with mutations at S21 (P ‫؍‬ 0.02). In addition, amino acid mutations at V13 (P ‫؍‬ 0.03) and E14 (P ‫؍‬ 0.01) were more common in the seven subjects with an HLA-A*02 allele. In summary, we have developed an assay that can identify associations between HLA class I alleles and HBV core gene amino acids that mutate in response to selection pressure. This is consistent with published evidence that CD8 ؉ T cells have a role in suppressing viral replication in inactive, HBeAg-negative chronic HBV infection. This assay may be useful for identifying the clinically significant HBV peptides that bind to common HLA class I molecules.The most potent nucleoside/nucleotide analogue drugs used to treat chronic hepatitis B reduce serum hepatitis B virus (HBV) DNA to undetectable levels in over 90% of subjects (5, 10). It was originally hoped that such a substantial reduction in viral titers would reverse T-cell tolerance for HBV antigens (17, 30) and lead to an immune response that permanently suppressed the virus, thus removing the need for expensive, lifelong drug therapy. However, HBeAg seroconversion rates of under 30% suggest that suppression of HBV replication is not sufficient to reverse the defects (4, 15) in the HBV peptidespecific CD8 ϩ T-cell compartment that occur in these patients. A therapeutic vaccine that stimulated a diverse repertoire of functional CD8 ϩ T cells could make a valuable contribution to management of chronic hepatitis B.The first step in designing a therapeutic vaccine that will suppress viral replication without exacerbating chronic hepatitis B (15) is to identify the HBV peptides that stimulate functional CD8 ϩ T cells by binding to the most common HLA class I alleles. These peptides may contribute to the antigen component of a vaccine and to the design of assays for use as correlates of immunity in trials of antiviral therapies. Although some of the HBV peptides that bind to four HLA-A alleles have been published (3,19,25,28), a much wider repertoire of peptide-HLA interactions needs to be identified. T...

Association between S21 substitution in the core protein of hepatitis B virus and fulminant hepatitis

“…A study from New Zealand reported that, in the core protein, S21 was one of the amino acids under significant positive selection pressure. 34 These data suggested that the S21 substitution favors the persistence of HBV in the late stage of the natural course of HBV chronic infection, despite the developed immunity.…”

HLA-DPPolymorphisms Affect the Outcomes of Chronic Hepatitis B Virus Infections, Possibly through Interacting with Viral Mutations

“…Associations between HLA class I genotypes/alleles and escape mutations in the HBV core gene have been investigated in chronic HBV infection (40,41). However, associations of HLA-DP polymorphisms with HBV mutations have not been reported.…”

Viral Adaptation to Host Immune Responses Occurs in Chronic Hepatitis B Virus (HBV) Infection, and Adaptation Is Greatest in HBV e Antigen-Negative Disease

“…In a recent study of New Zealand Tongans with chronic hepatitis B (CHB) with known specific HLA types (mainly HLA-B*4001 and HLA-B*5602 in patients with genotype C and D infections), 13 sites in the HBV genome under significant positive selection pressure were identified, and 5 of these sites were associated with a specific HLA type (1). One of these significant associations was between HLA-B*4001 and position 106 (equivalent to position 77 in reference 1), the same association found in our cohort, but by use of a different approach, identifying adaptation rather than selection.…”