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Prediction of conformational changes by single mutation in the hepatitis B virus surface antigen (HBsAg) identified in HBsAg-negative blood donors.

ABSTRACT: BACKGROUND: Selection of hepatitis B virus (HBV) by host immunity has been suggested to give rise to variants with amino acid substitutions at or around the 'a' determinant of the surface antigen (HBsAg), the main target of antibody neutralization and diagnostic assays. However, there have never been successful attempts to provide evidence for this hypothesis, partly because the 3 D structure of HBsAg molecules has not been determined. Tertiary structure prediction of HBsAg solely from its primary amino acid sequence may reveal the molecular energetic of the mutated proteins. We carried out this preliminary study to analyze the predicted HBsAg conformation changes of HBV variants isolated from Indonesian blood donors undetectable by HBsAg assays and its significance, compared to other previously-reported variants that were associated with diagnostic failure. RESULTS: Three HBV variants (T123A, M133L and T143M) and a wild type sequence were analyzed together with frequently emerged variants T123N, M133I, M133T, M133V, and T143L. Based on the Jameson-Wolf algorithm for calculating antigenic index, the first two amino acid substitutions resulted in slight changes in the antigenicity of the 'a' determinant, while all four of the comparative variants showed relatively more significant changes. In the pattern T143M, changes in antigenic index were more significant, both in its coverage and magnitude, even when compared to variant T143L. These data were also partially supported by the tertiary structure prediction, in which the pattern T143M showed larger shift in the HBsAg second loop structure compared to the others. CONCLUSIONS: Single amino acid substitutions within or near the 'a' determinant of HBsAg may alter antigenicity properties of variant HBsAg, which can be shown by both its antigenic index and predicted 3 D conformation. Findings in this study emphasize the significance of variant T143M, the prevalent isolate with highest degree of antigenicity changes found in Indonesian blood donors. This highlights the importance of evaluating the effects of protein structure alterations on the sensitivity of screening methods being used in detection of ongoing HBV infection, as well as the use of vaccines and immunoglobulin therapy in contributing to the selection of HBV variants.

SUBMITTER: Ie SI

PROVIDER: S-EPMC2998485 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Prediction of conformational changes by single mutation in the hepatitis B virus surface antigen (HBsAg) identified in HBsAg-negative blood donors.

Ie Susan I SI Thedja Meta D MD Roni Martono M Muljono David H DH

Virology journal 20101118

<h4>Background</h4>Selection of hepatitis B virus (HBV) by host immunity has been suggested to give rise to variants with amino acid substitutions at or around the 'a' determinant of the surface antigen (HBsAg), the main target of antibody neutralization and diagnostic assays. However, there have never been successful attempts to provide evidence for this hypothesis, partly because the 3 D structure of HBsAg molecules has not been determined. Tertiary structure prediction of HBsAg solely from it ...[more]

PMID: 21087462

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Project description:BackgroundThe epidemiology of hepatitis B virus (HBV) infection in the general population in Rwanda is not well known. This study examined the prevalence of HBV surface antigen (HBsAg) positivity and associated risk factors among people aged 25 years and over in an organized national screening campaign.MethodsThis is a cross-sectional study using data from a nationwide HBV screening campaign organized by the Rwanda Biomedical Centre from March to October 2018. This campaign targeted individuals aged > 25 years old from 24 of 30 districts of Rwanda. Sensitization was done through multimedia announcements, community health workers and local church leaders. During the campaign, a structured interview was administered by trained healthcare workers to collect information on socio-demographic, clinical and behavioral characteristics of participants; HBV screening was performed with HBsAg using enzyme-linked immunosorbent assays (ELISA) testing. Bivariate and multivariate logistic regressions were used to assess factors associated with HBsAg positivity in the screened participants.ResultsA total of 327,360 individuals were screened during the campaign. Overall 12,865(3.9%) were HBsAg positive. The highest prevalence (4.2%) was found in the 35-44-year-old group, but the difference from other groups was not significant (Odds Ratio [OR = 1.057, 95% Confidence Interval(CI) (0.904-1.235)]. Being male [OR = 1.348, 95% CI (1.30,1.40)]; being single [OR = 1.092, 95% CI (1.10-1.16)] compared to married; a previous positive TB screening test [OR = 2.352, 95% CI (1.63-3.39)]; history of surgical operation [OR = 1.082, 95% CI (1.00,1.17)]; exposure to traditional operational practices and scarification [OR = 1.187, 95% CI (1.13, 1.24)]; and having a person in the family with viral hepatitis [OR = 1.367, 95% CI (1.21, 1.53)] were significantly associated with HBV infection.ConclusionsThese data provide the first national estimate of the prevalence of HBsAg seropositivity and its associated factors in Rwanda. The study identified people with the highest risk of HBV infection who should be the priority of future prevention efforts in Rwanda and in similar settings.

Project description:BackgroundThe prevalence of chronic Hepatitis B Virus (HBV) infection is 2-4% in the Pakistani population, defining Pakistan as an intermediate prevalence country. In this study, hepatitis B surface antigen (HBsAg) reactive blood donations were screened using a combination of serological and molecular methods to identify immune escape HBV mutant strains and to determine the HBV genotypes and subtypes present in Pakistan.MethodsBlood donations were collected at the Armed Forces Institute of Transfusion (AFIT) located in northern Pakistan and the Hussaini Blood Bank (HBB) located in the south. From 2009 to 2013 a total of 706,575 donations were screened with 2.04% (14,409) HBsAg reactive. A total of 2055 HBsAg reactive specimens, were collected and screened using a monoclonal antibody based research assay to identify immune escape mutants followed by PCR amplification and DNA sequencing to identify the mutation present. DNA sequences obtained from 192 specimens, including mutant candidates and wild type strains, were analyzed for escape mutations, genotype, and HBsAg subtype.ResultsMutations were identified in approximately 14% of HBsAg reactive donations. Mutations at HBsAg amino acid positions 143-145 are the most common (46%) with the mutation serine 143 to leucine the most frequently occurring change (28%). While regional differences were observed, the most prevalent HBV strains are subgenotypes of D with subgenotype D1/subtype ayw2 accounting for the majority of infections; 90.2% at AFIT and 52.5% at HBB.ConclusionsThe high frequency of immune escape HBV mutants in HBV infected Pakistani blood donors highlights the need for more studies into the prevalence of escape mutants. Differences between vaccinated and unvaccinated populations, the correlation of escape mutant frequency with genotype, and impact of escape mutations in different genotype backgrounds on the performance of commercially available HBsAg assays represent avenues for further investigation.

Project description:HBsAg and HBeAg have gained traction as biomarkers of control and clearance during chronic hepatitis B virus infection (CHB). Improved understanding of the clearance correlates of these proteins could help inform improvements in patient-stratified care and advance insights into the underlying mechanisms of disease control, thus underpinning new cure strategies. We collected electronic clinical data via an electronic pipeline supported by the National Institute for Health Research Health Informatics Collaborative (NIHR HIC), adopting an unbiased approach to the generation of a robust longitudinal data set for adults testing HBsAg positive from a large UK teaching hospital over a 6-year period (2011 to 2016 inclusive). Of 553 individuals with CHB, longitudinal data were available for 319, representing >107,000 weeks of clinical follow-up. Among these 319 individuals, 13 (4%) cleared HBsAg completely. Among these 13, the HBsAg clearance rate in individuals on nucleos(t)ide analogue (NA) therapy (n = 4 [31%]; median clearance time,150 weeks) was similar to that in individuals not on NA therapy (n = 9 [69%]; median clearance time, 157 weeks). Those who cleared HBsAg were significantly older and less likely to be on NA therapy than nonclearers (P = 0.003 and P = 0.001, respectively). Chinese ethnicity was associated with HBeAg positivity (P = 0.025). HBeAg clearance occurred in individuals both on NA therapy (n = 24; median time, 49 weeks) and off NA therapy (n = 19; median time, 52 weeks). Improved insights into the dynamics of these biomarkers can underpin better prognostication and patient-stratified care. Our systematized approach to data collection paves the way for scaling up efforts to harness clinical data to address research questions and support improvements in clinical care.IMPORTANCE Advances in the diagnosis, monitoring, and treatment of hepatitis B virus (HBV) infection are urgently required if we are to meet international targets for elimination by the year 2030. Here we demonstrate how routine clinical data can be harnessed through an unbiased electronic pipeline, showcasing the significant potential for amassing large clinical data sets that can help to inform advances in patient care and provide insights that may help to inform new cure strategies. Our cohort from a large UK hospital includes adults from diverse ethnic groups that have previously been underrepresented in the literature. By tracking two protein biomarkers that are used to monitor chronic HBV infection, we provide new insights into the timelines of HBV clearance, both on and off treatment. These results contribute to improvements in individualized clinical care and may provide important clues into the immune events that underpin disease control.

Dataset Information

Prediction of conformational changes by single mutation in the hepatitis B virus surface antigen (HBsAg) identified in HBsAg-negative blood donors.

Publications

Prediction of conformational changes by single mutation in the hepatitis B virus surface antigen (HBsAg) identified in HBsAg-negative blood donors.

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