The preS deletion of hepatitis B virus (HBV) is associated with liver fibrosis progression in patients with chronic HBV infection

Li, Fan; Li, Xiaodong; Yan, Tao; Liu, Yan; Cheng, Yue; Xu, Zhihui; Shao, Qing; Liao, Huailin; Huang, Pengyu; Jin, Li; Chen, Guofeng; Xu, Da

doi:10.1007/s12072-018-9858-x

Cited by 9 publications

(16 citation statements)

References 26 publications

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“…These frequencies were less than previous reports of genotype C in CHB carriers [39], which indicates a lower risk of HCC in the population. The same result was also found in frequencies of mutation A2189C (12.85%), G1613A (8.94%), T1753C (8.38%), C1653T (5.59%), T53C (4.47%), T3098C (1.68%) and PreS deletion (2.23%, 4/179), which were also lower than mutation frequencies of genotype C in CHB patients in Asia [32,[34][35][36][37][38][39][40]. This indicates the clinical progress of CD recombinant seems genetically more temperate than genotype C which had caused the most liver disease and related death in China.…”

Section: Discussionsupporting

confidence: 72%

“…Previous studies reported that A1762T/G1764A double mutation in BCP (nt.1742-1849) was the strongest viral factor associated with the development of liver disease [20,31]. Other mutations, such as T53C, G1613A, C1653T, T1753C, A2189C, T3098C and PreS deletions were also reported associated with clinical progress [32][33][34][35][36][37][38]. In this study, the A1762T/G1764A double mutations were observed in 27.93% in HBV CD recombinant sequences.…”

Section: Discussionsupporting

confidence: 56%

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Complete genome analysis of hepatitis B virus in Qinghai-Tibet plateau: the geographical distribution, genetic diversity, and co-existence of HBsAg and anti-HBs antibodies

Shen

Zhang

et al. 2020

Virol J

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Background: The genetic variation and origin of Hepatitis B Virus (HBV) in Qinghai-Tibet Plateau were poorly studied. The coexistence of HBsAg and anti-HBs has been described as a puzzle and has never been reported in the indigenous population or in recombinant HBV sequences. This study aimed to report geographical distribution, genetic variability and seroepidemiology of HBV in southwest China. Methods: During 2014-2017, 1263 HBsAg positive serum were identified and 183 complete genome sequences were obtained. Serum samples were collected from community-based populations by a multistage random sampling method. Polymerase chain reaction (PCR) was used to amplify the HBV complete genome sequences. Then recombination, genetic variability, and serological analysis were performed. Results: (1) Of the 1263 HBsAg positive serum samples, there were significant differences between the distribution of seromarkers in Tibet and Qinghai. (2) Of 183 complete genome sequences, there were 130 HBV/CD1 (71.0%), 49 HBV/ CD2 (26.8%) and four HBV/C2 isolates (2.2%). Serotype ayw2 (96.1%) was the main serological subtype. (3) Several nucleotide mutations were dramatically different in CD1 and CD2 sequences. Clinical prognosis-related genetic variations such as nucleotide mutation T1762/A1764 (27.93%), A2189C (12.85%), G1613A (8.94%), T1753C (8.38%), T53C (4.47%) T3098C (1.68%) and PreS deletion (2.23%) were detected in CD recombinants. (4) From the inner land of China to the northeast boundary of India, different geographical distributions between CD1 and CD2 were identified. (5) Twenty-seven (2.14%) HBsAg/HBsAb coexistence serum samples were identified. S protein amino acid mutation and PreS deletion were with significant differences between HBsAg/HBsAb coexistence group and control group.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionsupporting

confidence: 56%

Complete genome analysis of hepatitis B virus in Qinghai-Tibet plateau: the geographical distribution, genetic diversity, and co-existence of HBsAg and anti-HBs antibodies

Shen

Zhang

et al. 2020

Virol J

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“…Common mutations in the preS region include mutated preS2 ATG codon to prevent M protein expression (34-39) and in-frame preS deletions to truncate the L, M, or both proteins (for a recent review, see (40). The latter include short deletions covering the preS1 ATG codon, and large deletions removing central/3' preS1 region or 5'/central preS2 region (35,(37)(38)(39)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51).…”

Section: Downloaded Frommentioning

confidence: 99%

Lost Small Envelope Protein Expression from Naturally Occurring PreS1 Deletion Mutants of Hepatitis B Virus Is Often Accompanied by Increased HBx and Core Protein Expression as Well as Genome Replication

Zhang

Yuan

et al. 2021

J Virol

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Hepatitis B virus (HBV) transcribes co-terminal mRNAs of 0.7-3.5kb from the 3.2-kb covalently closed circular (ccc) DNA, with the 2.1-kb RNA being most abundant. The 0.7-kb RNA produces HBx protein, a transcriptional transactivator, while the 3.5-kb pgRNA drives core and P protein translation as well as genome replication. The large (L) and small (S) envelope proteins are translated from the 2.4-kb and 2.1-kb RNAs, respectively, with majority of the S protein secreted as noninfectious subviral particles and detected as hepatitis B surface antigen (HBsAg). pgRNA transcription could inhibit transcription of subgenomic RNAs. The present study characterized naturally occurring in-frame deletions in the 3’ preS1 region, which not only codes for L protein but also serves as the promoter for 2.1-kb RNA. Human hepatoma cell line Huh7 was transiently transfected with subgenomic expression constructs for envelope (and HBx) proteins, dimeric construct, or one mimicking cccDNA. The results confirmed lost 2.1-kb RNA transcription and HBsAg production from many deletion mutants, which was accompanied by increased other (especially 2.4-kb) RNAs, intracellular HBx and core proteins, replicative DNA, but impaired virion and L protein secretion. Highest intracellular L protein was rather achieved by mutants with residual S protein expression or retaining matrix domain in L protein. Site-directed mutagenesis of a high replicating deletion mutant suggested that increased HBx protein expression and blocked virion secretion both contributed to high replication phenotype. Our findings could help explain why such deletions are selected at late stage of chronic HBV infection and how they contribute to viral pathogenesis. IMPORTANCE Expression of hepatitis B e antigen (HBeAg) and overproduction of hepatitis B surface antigen (HBsAg) by wild-type hepatitis B virus (HBV) are implicated in the induction of immune tolerance to achieve chronic infection. How HBV survives the subsequent immune clearance phase remains incompletely understood. Our previous characterization of core promoter mutations to reduce HBeAg production revealed ability of the 3.5-kb pgRNA to diminish transcription of co-terminal RNAs of 2.4kb, 2.1kb, and 0.7kb. The later stage of chronic HBV infection often selects for in-frame deletions in the preS region. Here we found that many 3’ preS1 deletions prevented transcription of the 2.1-kb RNA for HBsAg production, which was often accompanied by increased intracellular 3.5-, 0.7-, and especially 2.4-kb RNAs, HBx and core proteins, replicative DNA, but lost virion secretion. These findings established biological consequences of preS1 deletions, thus shedding light on why they are selected and how they contribute to hepatocarcinogenesis.

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“…Apart from the ability to avoid neutralization by vaccine-induced anti-HBs, these pre-S/S mutations may also have accounted for cases of occult HBV infection [31,41] . Furthermore, pre-S/S mutations have been found in association with various forms of acute and chronic liver disease, including fulminant hepatitis (FH), fibrosing cholestatic hepatitis (FCH) and cirrhosis [42][43][44] . Both pre-S1 and pre-S2 mutants led to defective secretion of mutant large surface antigens which then accumulated in ER, leading to ground glass hepatocytes (GGH) formation in chronic HBV infection [45,46] .…”

Section: The Association Between Pre-s Mutations and Hccmentioning

confidence: 99%

Pre-S2 and HBV associated hepatocellular carcinoma

Ying¹,

Qian²,

Fan³

2018

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Hepatitis B virus (HBV) infection is a primary cause of hepatocellular carcinoma (HCC). Under selection pressures of host immunity and/or immunoprophylaxis and antiviral therapies, HBV evolves by accumulating mutations in its genome. Several studies highlighted the considerable importance of HBV surface (HBs) protein mutants (pre-S/S variants) in tumorigenesis. Among those mutants, pre-S2 mutants have been recognized as "precursor lesions of HCC" and as risk factors for post-operative recurrence of HCC. Pre-S2 mutants play important roles in tumor progression and induce various mechanisms of tumorigenesis. These roles include that the cytoplasmic orientation of the pre-S2 domain is essential for the transcriptional activator C-terminally truncated middle surface protein (MHBst) which participates in the development of hepatocellular carcinoma. Pre-S2 mutants may also play important roles in HBV tumorigenesis by inducing both endoplasmic reticulum stress-dependent and endoplasmic reticulum (ER) stress-independent pathways. Because HCC has poor prognosis and its incidence is increasing, methods for the prevention and treatment of HCC should be comprehensive. Emerging treatments based on ER stress may provide a new strategy.

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The preS deletion of hepatitis B virus (HBV) is associated with liver fibrosis progression in patients with chronic HBV infection

Abstract: HBV preS deletion is positively associated with liver fibrosis progression in chronic HBV-infected patients. HBV preS2 deletion may serve as a warning indicator for liver fibrosis progression.

Cited by 9 publications

References 26 publications

Complete genome analysis of hepatitis B virus in Qinghai-Tibet plateau: the geographical distribution, genetic diversity, and co-existence of HBsAg and anti-HBs antibodies

Complete genome analysis of hepatitis B virus in Qinghai-Tibet plateau: the geographical distribution, genetic diversity, and co-existence of HBsAg and anti-HBs antibodies

Lost Small Envelope Protein Expression from Naturally Occurring PreS1 Deletion Mutants of Hepatitis B Virus Is Often Accompanied by Increased HBx and Core Protein Expression as Well as Genome Replication

Pre-S2 and HBV associated hepatocellular carcinoma

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