Occurrence of occult hepatitis B virus infection associated with envelope protein mutations according to anti-HBs carriage in blood donors

Wang, Jiawen; Zhang, Panli; Zeng, Jinfeng; Zheng, Xin; Ye, Xianlin; Zhu, Wenxiu; Fu, Yongshui; Candotti, Daniel; Allain, Jean‐Pierre; Li, Chengyao

doi:10.1016/j.ijid.2019.12.026

Cited by 21 publications

(28 citation statements)

References 38 publications

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“…Meanwhile, other kinds of E2 mutations (E2A/V/D) were observed in 1.1–7.8% of OBI strains ( p > 0.05) ( Table 1 ). In general, E2 mutations are specific and representative OBI-related mutations were found in 21.8% ( p < 0.05) of OBI subjects and none in the control group ( Table 1 ), which is consistent with a previous study in China ( Wang J. et al, 2020 ). Functional analysis showed that nearly all of the E2 mutations could significantly decrease extracellular and intracellular HBsAg level (except E2G in genotype B with increased intracellular HBsAg level) ( p < 0.05) ( Figures 1A,B ), which could partly explain the lack of HBsAg detection that characterized the occult HBV carriage in vivo .…”

Section: Discussionsupporting

confidence: 91%

E2 Site Mutations in S Protein Strongly Affect Hepatitis B Surface Antigen Detection in the Occult Hepatitis B Virus

et al. 2021

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The mechanism of occult hepatitis B infection (OBI) has not yet been fully clarified. Our previous research found that novel OBI-related mutation within S protein, E2G, could cause the hepatitis B surface antigen (HBsAg) secretion impairment, which resulted in intracellular accumulation in OBI of genotype B. Here, to further explore the role of E2 site mutations in the occurrence of OBI, we analyzed these site mutations among 119 OBI strains identified from blood donors. Meanwhile, 109 wild-type HBV strains (HBsAg positive/HBV DNA positive) were used as control group. Furthermore, to verify the E2 site mutations, two conservative 1.3-fold full-gene expression vectors of HBV genotype B and C (pHBV1.3B and pHBV1.3C) were constructed. Then, the E2 mutant plasmids on the basis of pHBV1.3B or pHBV1.3C were constructed and transfected into HepG2 cells, respectively. The extracellular and intracellular HBsAg were analyzed by electrochemical luminescence and cellular immunohistochemistry. The structural characteristics of S proteins with or without E2 mutations were analyzed using relevant bioinformatics software. E2 mutations (E2G/A/V/D) existed in 21.8% (26/119) of OBIs, while no E2 mutations were found in the control group. E2G/A/V/D mutations could strongly affect extracellular and intracellular level of HBsAg (p < 0.05). Notably, unlike E2G in genotype B that could cause HBsAg intracellular accumulation and secretion decrease (p < 0.05), E2G in genotype C could lead to a very significant HBsAg decrease both extracellularly (0.46% vs. pHBV1.3C) and intracellularly (11.2% vs. pHBV1.3C) (p < 0.05). Meanwhile, for E2G/A mutations, the relative intracellular HBsAg (110.7–338.3% vs. extracellular) and its fluorescence intensity (1.5–2.4-fold vs. with genotype-matched pHBV1.3B/C) were significantly higher (p < 0.05). Furthermore, N-terminal signal peptides, with a typical cleavage site for peptidase at positions 27 and 28, were exclusively detected in S proteins with secretion-defective mutants (E2G/A). Our findings suggest that: (1) E2G/A/V/D mutations were confirmed to significantly influence the detection of HBsAg, (2) the underlying mechanism of OBI caused by E2G mutation is quite different between genotype B and genotype C, and (3) E2G/A could produce a N-terminal truncated S protein, which might attribute to the HBsAg secretion impairment in the OBIs.

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Section: Discussionsupporting

confidence: 91%

E2 Site Mutations in S Protein Strongly Affect Hepatitis B Surface Antigen Detection in the Occult Hepatitis B Virus

et al. 2021

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“…Wt -wild-type, aa -amino acid. Deletions at the start of pre-S1 (causing truncated l-HBs proteins) and highlighted mutations in pre-S1 have all been associated with OBI in previous studies [38,51,52]. The mutated start codon of pre-S2 has been linked with an inability to express M-HBs [53].…”

Section: Defining and Characterising Obimentioning

confidence: 92%

Endemic HBV among hospital in-patients in Bangladesh, including evidence of occult infection

Chowdhury

McNaughton

Amin

et al. 2021

Journal of General Virology

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Bangladesh is one of the top-ten most heavily burdened countries for viral hepatitis, with hepatitis B (HBV) infections responsible for the majority of cases. Recombinant and occult HBV infections (OBI) have been reported previously in the region. We investigated an adult fever cohort (n=201) recruited in Dhaka, to determine the prevalence of HBV and OBI. A target-enrichment deep sequencing pipeline was applied to samples with HBV DNA >3.0 log10 IU ml−1. HBV infection was present in 16/201 (8 %), among whom 3/16 (19 %) were defined as OBI (HBsAg-negative but detectable HBV DNA). Whole genome deep sequences (WGS) were obtained for four cases, identifying genotypes A, C and D. One OBI case had sufficient DNA for sequencing, revealing multiple polymorphisms in the surface gene that may contribute to the occult phenotype. We identified mutations associated with nucleos(t)ide analogue resistance in 3/4 samples sequenced, although the clinical significance in this cohort is unknown. The high prevalence of HBV in this setting illustrates the importance of opportunistic clinical screening and DNA testing of transfusion products to minimise OBI transmission. WGS can inform understanding of diverse disease phenotypes, supporting progress towards international targets for HBV elimination.

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“…Thirdly, in occult HBV infection (OBI), HBsAg was undetectable with the existing detection methods. However, some specific mutations in preS/S gene were found in anti-HBs positive OBI samples [102] and might be adaptive substitutions selected under immune pressure. These are risk factors for virus reactivation under anti-HBs selection and changes of serological markers in OBI patients is worthy of clinical attention.…”

Section: Clinical Significance and Monitoring Suggestionsmentioning

confidence: 95%

Paradoxical HBsAg and anti-HBs coexistence among Chronic HBV Infections: Causes and Consequences

Jiang¹,

Chang²,

Yan³

et al. 2021

Int. J. Biol. Sci.

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Hepatitis B surface antigen (HBsAg) and Hepatitis B surface antibody (anti-HBs) were reported simultaneously among Hepatitis B virus (HBV) infections. HBsAg is a specific indicator of acute or chronic HBV infections, while anti-HBs is a protective antibody reflecting the recovery and immunity of hosts. HBsAg and anti-HBs coexist during seroconversion and then form immune complex, which is rare detected in clinical cases. However, with the promotion of vaccination and the application of various antiviral drugs, along with the rapid development of medical technology, the coexistence of HBsAg and anti-HBs has become more prevalent. Mutations in the viral genomes, immune status and genetic factors of hosts may contribute to the coexistence. Novel HBsAg assays, with higher sensitivity and ability to detect mutations or immune complexes, can also yield HBsAg/anti-HBs coexistence. The discovery of coexistence has shattered the idea of traditional serological patterns and raised questions about the effectiveness of vaccines. Worth noting is that HBsAg/anti-HBs double positivity is strongly associated with progressive liver diseases, especially hepatocellular carcinoma. In conclusion, viral mutations, host factors, and methodology impacts can all lead to the coexistence of HBsAg and anti-HBs. This coexistence is not an indicator of improvement, as an increased risk of adverse clinical outcomes still exists.

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Occurrence of occult hepatitis B virus infection associated with envelope protein mutations according to anti-HBs carriage in blood donors

Cited by 21 publications

References 38 publications

E2 Site Mutations in S Protein Strongly Affect Hepatitis B Surface Antigen Detection in the Occult Hepatitis B Virus

E2 Site Mutations in S Protein Strongly Affect Hepatitis B Surface Antigen Detection in the Occult Hepatitis B Virus

Endemic HBV among hospital in-patients in Bangladesh, including evidence of occult infection

Paradoxical HBsAg and anti-HBs coexistence among Chronic HBV Infections: Causes and Consequences

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