Novel HBsAg markers tightly correlate with occult HBV infection and strongly affect HBsAg detection

Svicher, Valentina; Cento, Valeria; Bernassola, Martina; Neumann-Fraune, Maria; Hemert, Formijn van; Chen, Mengjie; Salpini, Romina; Liu, Chang; Longo, Roberta; Visca, M.; Romanò, Sara; Micheli, Valeria; Bertoli, Ada; Gori, Caterina; Ceccherini‐Silberstein, Francesca; Sarrecchia, C.; Andreoni, Massimo; Angélico, M.; Ursitti, A.; Spanò, A.; Zhang, Jing Maria; Verheyen, Jens; Cappiello, Giuseppina; Perno, Carlo Federico

doi:10.1016/j.antiviral.2011.10.022

Cited by 78 publications

(90 citation statements)

References 31 publications

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“…First, this model does not consider missing genotypes and unobserved SNPs in the casecontrol sample, but this can be treated via imputation or EM algorithm incorporated in RBP model. Previous studies have shown that imputing untyped SNPsand missing genotypes from a reference panel can improve the power of disease association mapping (Svicher et al, 2011a). Second, the current model only considers one case and one control data.…”

Section: Resultsmentioning

confidence: 99%

“…Although this type of Bayesian recursive partition idea has been successfully used in several difference scenarios (Zhang et al, 2010;Svicher et al, 2011a;2011b) the current RBP model can be further improved in several ways. First, this model does not consider missing genotypes and unobserved SNPs in the casecontrol sample, but this can be treated via imputation or EM algorithm incorporated in RBP model.…”

Section: Resultsmentioning

confidence: 99%

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A Bayesian Method for Disentangling Dependent Structure of Epistatic Interaction

Zhang¹,

Qu²,

Lewis³

et al. 2011

American Journal of Biostatistics

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Problem statement:We propose a Bayesian method (RBP) to recursively infer the independence structure of epistatic interactions in case-control study. Approach: Based on the results of BEAM2, RBP can powerfully detect the marginal and conditional independence within interacting SNPs even in the complicated interaction cases. Results: We did extensive simulations to test RBP and compare it with stepwise logistic regression. Simulation results show that this approach is more powerful than stepwise logistic regression in detecting in marginal independence and conditional independence as well as more complicated dependence structure. We then applied BEAM2 and RBP on dbMHC Type 1 Diabetes (T1D) data and we found in MHC region, genes DRB1 and DQB1 are associated with T1D with saturated interaction structure which is consistent with the current knowledge of haplotype effect of these two genes on T1D. Conclusion: RBP is a powerful method to infer detailed dependence structures in epistatic interactions.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

A Bayesian Method for Disentangling Dependent Structure of Epistatic Interaction

Zhang¹,

Qu²,

Lewis³

et al. 2011

American Journal of Biostatistics

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“…Several studies have demonstrated that occult-associated mutations can lead to decreased detection of HBsAg, though the mechanisms vary (Hass et al, 2005;Huang et al, 2012;Jammeh et al, 2007;Martin et al, 2012;Svicher et al, 2012). For example, one study found that one occult-associated mutation altered the splicing of preS2/S mRNA and prevented post-transcriptional production of HBsAg but did not alter viral replication (Hass et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…For example, one study found that one occult-associated mutation altered the splicing of preS2/S mRNA and prevented post-transcriptional production of HBsAg but did not alter viral replication (Hass et al, 2005). Another study suggested that occult-associated mutations may introduce novel glycosylation sites or alter capsid/surface interactions (Svicher et al, 2012). Occult-associated mutations may exhibit increased HBsAg retention in cells, and fluorescence microscopy has shown localization to the endoplasmic reticulum (Biswas et al, 2013;Martin et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…Occult HBV also occurs more frequently in people with hepatitis C virus (HCV) and/or human immunodeficiency virus (HIV), suggesting that viral co-infections play a role (Cacciola et al, 1999;Kao et al, 2002;Mphahlele et al, 2006;Shire et al, 2004). Multiple studies have identified viral mutations that are associated with occult HBV and alter the ability of HBsAg to be produced, secreted from the cell or detected by commercial assays (Araujo et al, 2008;Candotti et al, 2006;Chaudhuri et al, 2004;Martin et al, 2010;Powell et al, 2014;Svicher et al, 2012). Though many occult HBV-associated mutations have been identified throughout the viral genome, functional analysis of these mutations is rare.…”

Section: Introductionmentioning

confidence: 99%

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Functional analysis of ‘a’ determinant mutations associated with occult HBV in HIV-positive South Africans

Powell

Boyce

Gededzha

et al. 2016

Journal of General Virology

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Occult hepatitis B is defined by the presence of hepatitis B virus (HBV) DNA in the absence of hepatitis B surface antigen (HBsAg). Occult HBV is associated with the development of hepatocellular carcinoma, reactivation during immune suppression, and virus transmission. Viral mutations contribute significantly to the occult HBV phenotype. Mutations in the 'a' determinant of HBsAg are of particular interest, as these mutations are associated with immune escape, vaccine escape and diagnostic failure. We examined the effects of selected occult HBV-associated mutations identified in a population of HIV-positive South Africans on HBsAg production in vitro. Mutations were inserted into two different chronic HBV backbones and transfected into a hepatocyte-derived cell line. HBsAg levels were quantified by enzymelinked immunosorbent assay (ELISA), while the detectability of mutant HBsAg was determined using an HA-tagged HBsAg expression system. Of the seven mutations analysed, four (S132P, C138Y, N146D and C147Y) resulted in decreased HBsAg expression in one viral background but not in the second viral background. One mutation (N146D) led to a decrease in HBsAg detected as compared to HA-tag, indicating that this mutation compromises the ability of the ELISA to detect HBsAg. The contribution of occult-associated mutations to the HBsAg-negative phenotype of occult HBV cannot be determined adequately by testing the effect of the mutation in a single viral background, and rigorous analysis of these mutations is required.

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Molecular analysis of the hepatitis B virus presurface and surface gene in patients from eastern China with occult hepatitis B

Huang

Qin

et al. 2013

Journal of Medical Virology

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This study was designed to detect and analyze mutations that occur within the presurface and surface (pre-S/S) gene of HBV in patients with occult hepatitis B, and determine their relationship to that disorder. Among 254 HBsAg negative samples of blood collected in eastern China, 183 were positive for anti-HBc alone, 61 were positive for anti-HBe alone, and 10 samples were positive for HBeAg. Within this group, 15 samples were found to be HBV DNA positive by real-time PCR and were designated Group I. A control group of 28 HBsAg positive samples were chosen at random from patients with chronic hepatitis B and designated Group II. The HBV pre-S/S gene was amplified by PCR and subjected to sequencing analysis. Occult hepatitis B was found in 1.6% of the patients with anti-HBc alone and in 3.3% of those with anti-HBe alone. Occult hepatitis B also was found in all HBsAg negative but HBeAg positive samples. Sequencing analysis showed a significant correlation between point mutations within the "a" determinant and occult hepatitis B (P < 0.0001), and a close relationship between pre-S deletion mutations and occult hepatitis B (P = 0.06). There were unique amino acid mutations at the G145 position other than G145R. The HBV DNA levels in patients with occult hepatitis B were significantly lower than those found in the control group. The "a" determinant mutations and pre-S deletions may play important roles in occult hepatitis B by affecting the expression, synthesis and secretion of the S protein and by impeding viral release and replication.

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Novel HBsAg markers tightly correlate with occult HBV infection and strongly affect HBsAg detection

Cited by 78 publications

References 31 publications

A Bayesian Method for Disentangling Dependent Structure of Epistatic Interaction

A Bayesian Method for Disentangling Dependent Structure of Epistatic Interaction

Functional analysis of ‘a’ determinant mutations associated with occult HBV in HIV-positive South Africans

Molecular analysis of the hepatitis B virus presurface and surface gene in patients from eastern China with occult hepatitis B

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