scholarly journals Modulation of Hepatitis B Virus Secretion by Naturally Occurring Mutations in the S Gene

2004 ◽  
Vol 78 (7) ◽  
pp. 3262-3270 ◽  
Author(s):  
Nasser Khan ◽  
Michael Guarnieri ◽  
Sang Hoon Ahn ◽  
Jisu Li ◽  
Yonghong Zhou ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Hepatitis B Surface Antigen ◽  
Point Mutations ◽  
Inhibitory Effect ◽  
Viral Envelope ◽  
Close Link ◽  
Naturally Occurring ◽  
B Virus ◽  
Secretion Efficiency

ABSTRACT Alteration in hepatitis B virus (HBV) secretion efficiency may have pathological consequences. Naturally occurring mutations that regulate virion secretion have not been defined. We recently identified HBV genomes displaying high (4B), substantially reduced (3.4), or negative (4C) virion secretion. In the present study, the underlying mutations were mapped. A T552C point mutation in the 4B genome was responsible for its enhanced virion secretion, whereas a G510A mutation in 3.4 and G660C in 4C impaired virus secretion. The three point mutations generate M133T, G119E, and R169P substitutions in the S domains of viral envelope proteins, respectively, without modifying the coding capacity of the overlapping polymerase gene. The mutated residues are predicted to lie in the luminal side of the endoplasmic reticulum (ER) or to be embedded in the ER membrane and thus are not involved in contact with core particles during envelopment. Of the two mutations inhibitory of virion secretion, G510A greatly reduced small envelope protein (hepatitis B surface antigen [HBsAg]) levels both inside cells and in culture medium, whereas G660C specifically abolished HBsAg secretion. Surprisingly, a T484G mutation in the 4B genome, generating an I110M substitution in the S domain, could also reduce HBsAg secretion and block virion secretion. However, its inhibitory effect was suppressed in the 4B genome by the T552C mutation, the enhancer of virion secretion. T552C can also override the inhibitory G510A mutation, but not the G660C mutation. These findings suggest a hierarchy in the regulation of virion secretion and a close link between defective virion secretion and impaired HBsAg formation or secretion.

scholarly journals Envelope Proteins of Hepatitis B Virus: Molecular Biology and Involvement in Carcinogenesis

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1124
Author(s):  
Jun Inoue ◽  
Kosuke Sato ◽  
Masashi Ninomiya ◽  
Atsushi Masamune
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Hepatitis B Surface Antigen ◽  
Envelope Proteins ◽  
Viral Envelope ◽  
Host Factors ◽  
Deletion Mutants ◽  
New Agents ◽  
Novel Drugs ◽  
B Virus

The envelope of hepatitis B virus (HBV), which is required for the entry to hepatocytes, consists of a lipid bilayer derived from hepatocyte and HBV envelope proteins, large/middle/small hepatitis B surface antigen (L/M/SHBs). The mechanisms and host factors for the envelope formation in the hepatocytes are being revealed. HBV-infected hepatocytes release a large amount of subviral particles (SVPs) containing L/M/SHBs that facilitate escape from the immune system. Recently, novel drugs inhibiting the functions of the viral envelope and those inhibiting the release of SVPs have been reported. LHBs that accumulate in ER is considered to promote carcinogenesis and, especially, deletion mutants in the preS1/S2 domain have been reported to be associated with the development of hepatocellular carcinoma (HCC). In this review, we summarize recent reports on the findings regarding the biological characteristics of HBV envelope proteins, their involvement in HCC development and new agents targeting the envelope.

scholarly journals 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

2021 ◽  
Author(s):  
Shuwen Fu ◽  
Jing Zhang ◽  
Quan Yuan ◽  
Qianru Wang ◽  
Qiang Deng ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Protein Expression ◽  
Hepatitis B Surface Antigen ◽  
Genome Replication ◽  
L Protein ◽  
Naturally Occurring ◽  
Core Proteins ◽  
B Virus ◽  
Chronic Hbv

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.

How Far we are towards Eradication of HBV Infection

2015 ◽  
Vol 24 (4) ◽  
pp. 473-479 ◽  
Author(s):  
Mihai Voiculescu
Keyword(s):  
Immune Response ◽  
Hepatitis B Virus ◽  
T Cell ◽  
Hepatitis B ◽  
T Cell Receptors ◽  
Hepatitis B Surface Antigen ◽  
Hbv Infection ◽  
Major Health Problem ◽  
Cell Receptors ◽  
B Virus

Hepatitis B virus (HBV) infection is a major health problem with an important biological and a significant socio-economic impact all over the world. There is a high pressure to come up with a new and more efficient strategy against HBV infection, especially after the recent success of HCV treatment. Preventing HBV infection through vaccine is currently the most efficient way to decrease HBV-related cirrhosis and liver cancer incidence, as well as the best way to suppress the HBV reservoir. The vaccine is safe and efficient in 80-95% of cases. One of its most important roles is to reduce materno-fetal transmission, by giving the first dose of vaccine in the first 24 hours after birth. Transmission of HBV infection early in life is still frequent, especially in countries with high endemicity.Successful HBV clearance by the host is immune-mediated, with a complex combined innate and adaptive cellular and humoral immune response. Different factors, such as the quantity and the sequence of HBV epitope during processing by dendritic cells and presenting by different HLA molecules or the polymorphism of T cell receptors (TOL) are part of a complex network which influences the final response. A new potential therapeutic strategy is to restore T-cell antiviral function and to improve innate and adaptive immune response by immunotherapeutic manipulation.It appears that HBV eradication is far from being completed in the next decades, and a new strategy against HBV infection must be considered. Abbreviations: ALT: alanine aminotransferase; APC: antigen presenting cells; cccDNA: covalently closed circular DNA; HBIG: hepatitis B immunoglobulin; HbsAg: hepatitis B surface antigen; HBV: hepatitis B virus; HCC: hepatocellular carcinoma; CTL: cytotoxic T lymphocyte; IFN: interferon; NUC: nucleos(t)ide analogues; pg RNA: pre genomic RNA; TLR: toll-like receptors; TOL: T cell receptors.

scholarly journals Complete-genome analysis of hepatitis B virus from wild-born chimpanzees in central Africa demonstrates a strain-specific geographical cluster

2007 ◽  
Vol 88 (10) ◽  
pp. 2679-2685 ◽  
Author(s):  
Maria Makuwa ◽  
Sandrine Souquière ◽  
Olivier Bourry ◽  
Pierre Rouquet ◽  
Paul Telfer ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Complete Genome ◽  
Geographical Origin ◽  
Hepatitis B Surface Antigen ◽  
Central Africa ◽  
High Plasma ◽  
B Virus ◽  
Geographical Cluster ◽  
Loads Analysis

In order to determine whether geographical or species clustering accounts for the distribution of hepatitis B virus (HBV) in subspecies of chimpanzees in Africa, four complete chimpanzee HBV (ChHBV) genome sequences were obtained from eight hepatitis B surface antigen-positive wild-born chimpanzees from Cameroon, Republic of Congo and Gabon. The serological profiles of these chimpanzees corresponded to the acute or chronic highly replicative phase of HBV infection, as confirmed by high plasma HBV loads. Analysis of the sequence alignment of 256 aa (S region) from the eight HBV-infected chimpanzees allowed us to determine the HBV amino acid patterns specific to each chimpanzee subspecies and to their geographical origin. Phylogenetic analysis of both the S region and the complete genome confirmed this distinctive clustering of eight novel ChHBV strains within Pan troglodytes. The strong phylogenetic associations of ChHBV sequences with both chimpanzee subspecies and their geographical origin were therefore confirmed.

scholarly journals Hepatitis B Core-Related Antigen as Surrogate Biomarker of Intrahepatic Hepatitis B Virus Covalently-Closed-Circular DNA in Patients with Chronic Hepatitis B: A Meta-Analysis

Diagnostics ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 187
Author(s):  
Gian Paolo Caviglia ◽  
Angelo Armandi ◽  
Chiara Rosso ◽  
Davide Giuseppe Ribaldone ◽  
Rinaldo Pellicano ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Hepatitis B Surface Antigen ◽  
Meta Analysis ◽  
Circular Dna ◽  
Non Invasive ◽  
Hbv Cccdna ◽  
B Virus ◽  
Chronic Hbv ◽  
Intrahepatic Hbv

Hepatitis B virus (HBV) covalently-closed-circular (ccc)DNA is the key molecule responsible for viral persistence within infected hepatocytes. The evaluation of HBV cccDNA is crucial for the management of patients with chronic HBV infection and for the personalization of treatment. However, the need for liver biopsy is the principal obstacle for the assessment of intrahepatic HBV cccDNA. In the last decade, several studies have investigated the performance of hepatitis B core-related antigen (HBcrAg) as a surrogate of HBV cccDNA amount in the liver. In this meta-analysis, we collected 14 studies (1271 patients) investigating the correlation between serum HBcrAg and intrahepatic HBV cccDNA. Serum HBcrAg showed a high correlation with intrahepatic HBV cccDNA (r = 0.641, 95% confidence interval (CI) 0.510–0.743, p < 0.001). In a head-to-head comparison, we observed that the performance of HBcrAg was significantly superior to that of hepatitis B surface antigen (r = 0.665 vs. r = 0.475, respectively, p < 0.001). Subgroup analysis showed that the correlation between HBcrAg and intrahepatic HBV cccDNA was high, both in hepatitis B e antigen-positive and -negative patients (r = 0.678, 95% CI 0.403–0.840, p < 0.001, and r = 0.578, 95% CI 0.344–0.744, p < 0.001, respectively). In conclusion, the measurement of serum HBcrAg qualifies as a reliable non-invasive surrogate for the assessment of an intrahepatic HBV cccDNA reservoir.

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