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Effects of amino acid substitutions in hepatitis B virus surface protein on virion secretion, antigenicity, HBsAg and viral DNA.

ABSTRACT: BACKGROUND & AIMS:As important virological markers, serum hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA levels show large fluctuations among chronic hepatitis B patients. The aim of this study was to reveal the potential impact and mechanisms of amino acid substitutions in small hepatitis B surface proteins (SHBs) on serum HBsAg and HBV DNA levels. METHODS:Serum samples from 230 untreated chronic hepatitis B patients with genotype C HBV were analyzed in terms of HBV DNA levels, serological markers of HBV infection and SHBs sequences. In vitro functional analysis of the identified SHBs mutants was performed. RESULTS:Among 230 SHBs sequences, there were 39 (16.96%) sequences with no mutation detected (wild-type) and 191 (83.04%) with single or multiple mutations. SHBs consist of 226 amino acids, of which 104 (46.02%) had mutations in our study. Some mutations (e.g., sE2G, sL21S, sR24K, sT47A/K, sC69stop (sC69?), sL95W, sL98V, and sG145R) negatively correlated with serum HBsAg levels. HBsAg and HBV DNA levels from this group of patients had a positive correlation (r=0.61, p<0.001). In vitro analysis showed that these mutations reduced extracellular HBsAg and HBV DNA levels by restricting virion secretion and antibody binding capacity. Virion secretion could be rescued for sE2G, sC69?, and sG145R by co-expression of wild-type HBsAg. CONCLUSION:The serum HBsAg levels were lower in untreated CHB patients with novel SHBs mutations outside the major antigenic region than those without mutations. Underlying mechanisms include impairment of virion secretion and lower binding affinity to antibodies used for HBsAg measurements. LAY SUMMARY:The hepatitis B surface antigen (HBsAg) is a major viral protein of the hepatitis B virus (HBV) secreted into patient blood serum and its quantification value serves as an important marker for the evaluation of chronic HBV infection and antiviral response. We found a few new amino acid substitutions in HBsAg associated with lower serum HBsAg and HBV DNA levels. These different substitutions might impair virion secretion, change the ability of HBsAg to bind to antibodies, or impact HBV replication. These could all result in decreased detectable levels of serum HBsAg. The factors affecting circulating HBsAg level and HBsAg detection are varied and caution is needed when interpreting clinical significance of serum HBsAg levels. Clinical trial number: NCT01088009.

SUBMITTER: Xiang KH

PROVIDER: S-EPMC5523976 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Effects of amino acid substitutions in hepatitis B virus surface protein on virion secretion, antigenicity, HBsAg and viral DNA.

Xiang Kuan-Hui KH Michailidis Eleftherios E Ding Hai H Peng Ya-Qin YQ Su Ming-Ze MZ Li Yao Y Liu Xue-En XE Dao Thi Viet Loan VL Wu Xian-Fang XF Schneider William M WM Rice Charles M CM Zhuang Hui H Li Tong T

Journal of hepatology 20160917 2

<h4>Background & aims</h4>As important virological markers, serum hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA levels show large fluctuations among chronic hepatitis B patients. The aim of this study was to reveal the potential impact and mechanisms of amino acid substitutions in small hepatitis B surface proteins (SHBs) on serum HBsAg and HBV DNA levels.<h4>Methods</h4>Serum samples from 230 untreated chronic hepatitis B patients with genotype C HBV were analyzed in terms ...[more]

PMID: 27650283

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Project description:BACKGROUND: During 2009 to 2012, Thailand had encountered 4 distinctive waves of the 2009 pandemic influenza A(H1N1) (H1N1pdm) outbreaks. Considering the RNA nature of the influenza viral genome, a mutation in hemagglutinin (HA) gene which led to change in antigenicity of the strains circulating during those epidemic periods is anticipated. It is also uncertain whether the A/California/07/2009 (H1N1) (CA/07) vaccine strain still confers protective immunity against those evolved viruses, the causative agents of the later epidemic waves. METHODS: HA gene segments of 10 H1N1pdm isolates obtained during 2009 to 2012 were sequenced and phylogenetically analysed using ClustalW and MEGA5 programs. A total of 124 convalescent serum samples collected from patients naturally infected during 3 epidemic waves were employed as tools to investigate for antigenic change in HA of these 10 circulating H1N1pdm viruses by hemagglutination inhibition (HI) assay. RESULTS: A phylogenetic analysis showed that the 10 virus isolates were grouped into 4 clusters corresponding to the time of 4 consecutive outbreaks. An accumulation of amino acid substitutions in HA was observed in viruses derived from the late epidemic waves. Significantly lower antibody titers were observed when CA/07 was tested against convalescent sera collected from the 3 waves (p<0.05) compared to most of Thai isolates; and significantly lower antibody titers were also obtained when virus isolates, retrieved from the third epidemic wave were tested against convalescent sera collected during the first and second wave. These results were suggestive of change in antigenicity of the evolved viruses. Our results also showed some mutation position residing outside the previously reported antigenic site that may involve in an alteration of the viral antigenicity. CONCLUSIONS: Our study demonstrated that convalescent sera collected from individuals naturally infected with H1N1pdm virus were successfully used to reveal a statistically significant change in antibody titers against the currently evolved H1N1pdm viruses as determined by HI assay. Nevertheless, the antibody titers of individual serum against various viruses were less than 4-folded difference as compared to that against the CA/07 vaccine strain. Therefore, CA/07 is still a potent vaccine strain for those evolved H1N1pdm viruses.

Project description:Background & aimsSofosbuvir is a frequently used pan-genotype inhibitor of hepatitis C virus (HCV) polymerase. This drug eliminates most chronic HCV infections, and resistance-associated substitutions in the polymerase are rare. However, HCV genotype 3 responds slightly less well to sofosbuvir-based therapies than other genotypes. We collected data from England's National Health Service Early Access Program to search for virus factors associated with sofosbuvir treatment failure.MethodsWe collected patient serum samples and used the capture-fusion assay to assess viral sensitivity to sofosbuvir in 14 HCV genotype 3 samples. We identified polymorphisms associated with reduced response and created modified forms of HCV and replicons containing the substitutions of interest and tested their sensitivity to sofosbuvir and ribavirin. We examined the effects of these polymorphisms by performing logistic regression multivariate analysis on their association with sustained virologic response in a separate cohort of 411 patients with chronic HCV genotype 3 infection who had been treated with sofosbuvir and ribavirin, with or without pegylated interferon.ResultsWe identified a substitution in the HCV genotype 3a NS5b polymerase at amino acid 150 (alanine [A] to valine [V]), V at position 150 was observed in 42% of patients) with a reduced response to sofosbuvir in virus replication assays. In patients treated with sofosbuvir-containing regimens, the A150V variant was associated with a reduced response to treatment with sofosbuvir and ribavirin, with or without pegylated interferon. In 326 patients with V at position 150, 71% achieved an sustained virologic response compared to 88% with A at position 150. In cells, V at position 150 reduced the response to sofosbuvir 7-fold. We found that another rare substitution, glutamic acid (E) at position 206, significantly reduced the response to sofosbuvir (8.34-fold reduction); the combinations of V at position 150 and E at position 206 reduced the virus response to sofosbuvir 35.77-fold. Additionally, in a single patient, we identified 5 rare polymorphisms that reduced sensitivity to sofosbuvir our cell system.ConclusionsA common polymorphism, V at position 150 in the HCV genotype 3a NS5b polymerase, combined with other variants, reduces the virus response to sofosbuvir. Clinically, infection with HCV genotype 3 containing this variant reduces odds of sustained virologic response. In addition, we identified rare combinations of variants in HCV genotype 3 that reduce response to sofosbuvir.

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Effects of amino acid substitutions in hepatitis B virus surface protein on virion secretion, antigenicity, HBsAg and viral DNA.

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Effects of amino acid substitutions in hepatitis B virus surface protein on virion secretion, antigenicity, HBsAg and viral DNA.

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