N-glycosylation mutations within hepatitis B virus surface major hydrophilic region contribute mostly to immune escape

SUMMARYMutations in the major hydrophilic region (MHR) of the surface antigen of hepatitis B virus (HBV) may result in vaccine escape, failure of immunotherapy and antiviral resistance. These mutants may be transmitted and constitute a public health threat. We aimed to determine the prevalence of MHR mutations of HBV in areas of high endemicity in Guangxi, China. HBV surface gene was analysed from 278 HBsAg-positive asymptomatic individuals recruited from Guangxi using cluster sampling. Three genotypes, B, C and I, were identified. The overall prevalence of MHR mutations is 17·6%. The prevalence of MHR mutations in genotype B (15·1%) is not significantly different from that in genotype C (16·4%). However, the prevalence in subgenotype C5 (31·1%) is significantly higher than in subgenotype C2 (13·0%) (χ2= 6·997,P< 0·05). The prevalence of escape mutations and overlapping polymerase substitutions in subgenotype C5 is significantly higher than in subgenotypes B2 and C2. In total, 7·9% of MHR mutants are escape mutations and 72·1% of MHR mutations produced amino-acid changes in the overlapping polymerase, including resistance mutations to entecavir. Our results suggest that the prevalence of MHR mutations varies with subgenotype. The prevalence of escape mutations and polymerase mutations may be associated with subgenotype.

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Hepatitis B virus surface antigen impairs myeloid dendritic cell function: a possible immune escape mechanism of hepatitis B virus

Immunology ◽

10.1111/j.1365-2567.2008.02896.x ◽

2009 ◽

Vol 126 (2) ◽

pp. 280-289 ◽

Cited By ~ 130

Author(s):

Marjoleine L. Op den Brouw ◽

Rekha S. Binda ◽

Mark H. van Roosmalen ◽

Ulrike Protzer ◽

Harry L. A. Janssen ◽

...

Keyword(s):

Hepatitis B Virus ◽

Dendritic Cell ◽

Hepatitis B ◽

Cell Function ◽

Immune Escape ◽

Myeloid Dendritic Cell ◽

Dendritic Cell Function ◽

Virus Surface ◽

B Virus ◽

Immune Escape Mechanism

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Endocytosis of Hepatitis B Immune Globulin into Hepatocytes Inhibits the Secretion of Hepatitis B Virus Surface Antigen and Virions

Journal of Virology ◽

10.1128/jvi.77.16.8882-8892.2003 ◽

2003 ◽

Vol 77 (16) ◽

pp. 8882-8892 ◽

Cited By ~ 61

Author(s):

Ralf Schilling ◽

Samreen Ijaz ◽

Michail Davidoff ◽

Jia Yee Lee ◽

Stephen Locarnini ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Surface Antigen ◽

Immune Escape ◽

Dependent Manner ◽

Wild Type ◽

Virus Surface ◽

Virus Surface Antigen ◽

B Virus ◽

Specific Igg

ABSTRACT Hepatitis B immunoglobulin is used for prophylaxis against hepatitis B virus (HBV) and is thought to act by neutralization of virions and hepatitis B virus surface antigen (HBsAg)-containing particles in circulation. Using a panel of hepatocyte-derived cell lines, the present study investigated in vitro whether HBs-specific immunoglobulin G (IgG) is internalized in hepatocytes and whether it interacts with HBsAg in the cells. By immunoelectron microscopy and immunoblotting, human IgG and FcRn receptor for IgG were demonstrated on cellular membranes and in cytoplasmic extracts, irrespective of the HBsAg status of the cells. Furthermore, HBsAg and anti-HBs were shown to be colocalized in the same cellular compartment by two-color confocal microscopy. Endocytosis of HBs-specific IgG caused intracellular accumulation of HBsAg in a dose-dependent manner and inhibited the secretion of HBsAg and HBV virions from the cells. These effects were not observed with F(ab)2 fragments or nonimmune IgG as controls. The specificity of intracellular HBsAg- anti-HBs interaction was further investigated in cells transfected with HBV genomes expressing wild-type HBsAg or immune escape HBsAg (with a G145R mutation). Monoclonal anti-HBs markedly reduced the secretion of wild-type HBsAg, while the secretion of mutant HBsAg was not affected. These results suggest that HBs-specific IgG binds to hepatocytes and interacts with HBsAg within the cells. This may be relevant for the selection of surface antibody escape mutations.

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Ultradeep Sequencing for Detection of Quasispecies Variants in the Major Hydrophilic Region of Hepatitis B Virus in Indonesian Patients

Journal of Clinical Microbiology ◽

10.1128/jcm.00602-15 ◽

2015 ◽

Vol 53 (10) ◽

pp. 3165-3175 ◽

Cited By ~ 15

Author(s):

Laura Navika Yamani ◽

Yoshihiko Yano ◽

Takako Utsumi ◽

Juniastuti ◽

Hadi Wandono ◽

...

Keyword(s):

Chronic Hepatitis ◽

Liver Disease ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Viral Population ◽

Advanced Liver Disease ◽

Major Hydrophilic Region ◽

B Virus ◽

Hbsag Titer ◽

Hydrophilic Region

Quasispecies of hepatitis B virus (HBV) with variations in the major hydrophilic region (MHR) of the HBV surface antigen (HBsAg) can evolve during infection, allowing HBV to evade neutralizing antibodies. These escape variants may contribute to chronic infections. In this study, we looked for MHR variants in HBV quasispecies using ultradeep sequencing and evaluated the relationship between these variants and clinical manifestations in infected patients. We enrolled 30 Indonesian patients with hepatitis B infection (11 with chronic hepatitis and 19 with advanced liver disease). The most common subgenotype/subtype of HBV was B3/adw (97%). The HBsAg titer was lower in patients with advanced liver disease than that in patients with chronic hepatitis. The MHR variants were grouped based on the percentage of the viral population affected: major, ≥20% of the total population; intermediate, 5% to <20%; and minor, 1% to <5%. The rates of MHR variation that were present in the major and intermediate viral population were significantly greater in patients with advanced liver disease than those in chronic patients. The most frequent MHR variants related to immune evasion in the major and intermediate populations were P120Q/T, T123A, P127T, Q129H/R, M133L/T, and G145R. The major population of MHR variants causing impaired of HBsAg secretion (e.g., G119R, Q129R, T140I, and G145R) was detected only in advanced liver disease patients. This is the first study to use ultradeep sequencing for the detection of MHR variants of HBV quasispecies in Indonesian patients. We found that a greater number of MHR variations was related to disease severity and reduced likelihood of HBsAg titer.

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rt269I Type of Hepatitis B Virus (HBV) Polymerase versus rt269L Is More Prone to Mutations within HBV Genome in Chronic Patients Infected with Genotype C2: Evidence from Analysis of Full HBV Genotype C2 Genome

Microorganisms ◽

10.3390/microorganisms9030601 ◽

2021 ◽

Vol 9 (3) ◽

pp. 601

Author(s):

Hyein Jeong ◽

Dong Hyun Kim ◽

Yu-Min Choi ◽

HyeLim Choi ◽

Donghyun Kim ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Immune Escape ◽

Statistical Significance ◽

Hbv Dna ◽

Type I ◽

Chronic Patients ◽

Hbv Genotype ◽

Major Hydrophilic Region ◽

B Virus

Recently, it has been reported that the rt269I type of hepatitis B virus (HBV) polymerase (Pol) versus the rt269L type is more significantly related to lower viral replication and HBeAg negative infections in chronic hepatitis B (CHB) patients of genotype C2. In this study, we compared mutation rates within HBV genomes between rt269L and rt269I using a total of 234 HBV genotype C2 full genome sequences randomly selected from the HBV database (115 of rt269L and 119 of rt269I type). When we applied the Benjamini and Hochberg procedure for multiple comparisons, two parameters, dN and d, at the amino acids level in the Pol region were significantly higher in the rt269I type than in the rt269L type. Although it could not reach statistical significance from the Benjamini and Hochberg procedure, nonsynonymous (NS) mutations in the major hydrophilic region (MHR) or “a” determinant in the surface antigens (HBsAg ORF) related to host immune escape or vaccine escape are more frequently generated in rt269I strains than in rt269L. We also found that there are a total of 19 signature single nucleotide polymorphisms (SNPs), of which 2 and 17 nonsynonymous mutation types were specific to rt269L and rt269I, respectively: Of these, most are HBeAg negative infections (preC-W28*, X-V5M and V131I), lowered HBV DNA or virion production (C-I97F/L, rtM204I/V) or preexisting nucleot(s)ide analog resistance (NAr) (rtN139K/H, rtM204I/V and rtI224V) or disease severity (preC-W28*, C-I97F/L, C-Q182K/*, preS2-F141L, S-L213I/S, V/L5M, T36P/S/A, V131I, rtN139K/H, rtM204I/V and rtI224V). In conclusion, our data showed that rt269I types versus rt269L types are more prone to overall genome mutations, particularly in the Pol region and in the MHR or “a” determinant in genotype C2 infections and are more prevalent in signature NS mutations related to lowered HBV DNA replication, HBsAg and HBeAg secretion and potential NAr variants and hepatocellular carcinoma (HCC), possibly via type I interferon (IFN-I)-mediated enhanced inflammation. Our data suggest that rt269L types could contribute to liver disease progression via the generation of immune escape or enhanced persistent infection in chronic patients of genotype C2.

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