RESUMO
Identification of the full repertoire of hepatitis B virus (HBV) peptides that are presented to CD8+ T cells by common HLA class I alleles will be useful for designing immunotherapies for chronic hepatitis B. One hundred and seventy five cloned sequences containing the pre-S/S and P open reading frames (ORF) of the HBV were obtained from serum HBV-DNA of HBeAg-positive (n=4) and HBeAg-negative (inactive healthy carriers (IHC), n=16) Tongan subjects with an inactive chronic HBV infection. In addition, 34 and 32 sequences were obtained 5.2±1.4 (mean±SD) years apart from eight subjects. PAML was used to identify codons in the pre-S/S and P ORFs that were under positive selection pressure (ω>1). The number of non-synonymous substitutions in these codons was compared in IHC who were homozygous for either HLA-B∗4001 (n=9) or HLA-B*5602 (n=7), and who were either positive (n=6) or negative (n=10) for HLA-A*02. 34 codons in the pre-S/S and 11 codons in the P ORFs were under positive selection pressure. There was a higher number of non-synonymous substitutions in these codons in HBeAg-negative versus HBeAg-positive subjects in the P (p=0.02) but not the pre-S/S (p=0.64) ORF. There was no association between any HLA class I allele and non-synonymous substitutions in these codons. There was no increase in positive selection pressure on the pre-S/S and P ORFs with time. In conclusion, we could not find HLA class I-restricted selection pressure on any pre-S/S or P ORF amino acid; raising the possibility that peptide-based immunotherapies for chronic hepatitis B may not require peptides from these ORFs.
Assuntos
Produtos do Gene pol/genética , Vírus da Hepatite B/genética , Hepatite B Crônica/genética , Hepatite B Crônica/virologia , Fases de Leitura Aberta , Proteínas do Envelope Viral/genética , Adulto , Linfócitos T CD8-Positivos/imunologia , Feminino , Vírus da Hepatite B/imunologia , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Mutação de Sentido Incorreto , Seleção Genética , Soro/virologiaRESUMO
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.
Assuntos
Vírus da Hepatite B/genética , Antígenos de Histocompatibilidade Classe I/genética , Evasão da Resposta Imune/genética , Mutação , Alelos , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Hepatite B/epidemiologia , Hepatite B/genética , Hepatite B/imunologia , Vírus da Hepatite B/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Nova Zelândia/epidemiologia , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Seleção Genética , Tonga/epidemiologia , Proteínas do Core Viral/genética , Proteínas do Core Viral/imunologiaRESUMO
OBJECTIVE: To examine associations between A1C concentration and mortality in a New Zealand population. RESEARCH DESIGN AND METHODS: During a Hepatitis Foundation screening campaign for hepatitis B (1999-2001), participants were offered A1C testing. The participants were anonymously linked to the national mortality collection to 31 December 2004. Hazard ratios (HRs) and 95% CIs adjusted for age, ethnicity, smoking, and sex were estimated using Cox regression. RESULTS: There were 47,904 participants (71% Mâori, 12% Pacific, 5% Asian, and 12% other). A1C measurements were categorized as <4.0% (n = 142), 4.0 to <5.0% (reference category; n = 12,867), 5.0 to <6.0% (n = 30,222), 6.0 to <7.0% (n = 2,669), and >or=7.0% (n = 1,596); there were also 408 participants with a previous diabetes diagnosis. During the follow-up period, 815 individuals died. In those without a prior diabetes diagnosis, there were steadily increasing HRs from the A1C reference category to the highest category (>or=7.0%; HR 2.36 [95% CI 1.72-3.25]). As well as all-cause mortality, A1C was associated with mortality from diseases of the circulatory system; endocrine, nutritional, metabolic, and immunity disorders; and other and unknown causes. Mortality was also elevated in those with a prior diabetes diagnosis (5.19 [3.67-7.35]), but this was only partially explained by their elevated A1C levels. CONCLUSIONS: This is the largest study to date of A1C levels and subsequent mortality risk. It confirms previous findings that A1C levels are strongly associated with subsequent mortality in both men and women without a prior diabetes diagnosis.
Assuntos
Causas de Morte , Hemoglobinas Glicadas/metabolismo , Diabetes Mellitus/mortalidade , Etnicidade , Feminino , Inquéritos Epidemiológicos , Humanos , Masculino , Nova Zelândia/epidemiologia , Reprodutibilidade dos Testes , Fatores de Risco , Fumar/epidemiologiaRESUMO
AIM: To report on screening coverage and the distribution of HBsAg (a marker of chronic hepatitis B virus infection) among participants in the New Zealand Hepatitis B Screening Programme. METHOD: Coverage and crude and age-standardised prevalence rates of HBsAg by age group, sex, ethnic group, and region were calculated from data held by the two providers and the New Zealand 2001 Census. RESULTS: 177,000 people were tested for hepatitis B virus infection (51% of the programme targets and 27% of Census 2001 eligible population), with highest coverage among women (28.9%) and Pacific people (34.9%). Overall, 5.7% (10,176) of participants were HBsAg-positive and there were significant regional, ethnic group, and gender differences. 5.6% of Maori, 7.3% of Pacific people, and 6.2% of Asians were HBsAg-positive, and men were more likely to test HBsAg-positive (6.1%) than women (5.4%). CONCLUSIONS: Previous estimates of HBsAg prevalence among Maori and Pacific people from smaller surveys were confirmed and new information obtained about the distribution of hepatitis B virus infection among Pacific Islands and Asian populations in New Zealand. Opportunistic screening of adults in these populations should continue in order to identify others with (as yet undetected) infection. Regular follow-up of people with chronic hepatitis B virus infection should also continue. Ongoing outcome monitoring is now needed to judge whether this unique programme has been an effective component of New Zealand's hepatitis B control strategy and whether it is a worthwhile investment of resources.
