Secretion and Antigenicity of Hepatitis B Virus Small Envelope Proteins Lacking Cysteines in the Major Antigenic Region

Mangold, C. M. T.; Unckell, F; Werr, Margaret; Streeck, Rolf E.

doi:10.1006/viro.1995.1435

Cited by 94 publications

(86 citation statements)

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“…The AGL is known to bear the major HBVneutralizing epitopes (30) and a conserved immunodominant determinant, referred to as "a." It also contains eight cysteine residues described as engaged in disulfide bonds that are in-strumental in defining the structure of the "a" determinant (25,27). Furthermore, cysteines at positions 121 and 124 constitute a CxxC motif that is generally found on protein-disulfide isomerase (PDI)-related proteins (38).…”

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confidence: 99%

Entry of Hepatitis Delta Virus Requires the Conserved Cysteine Residues of the Hepatitis B Virus Envelope Protein Antigenic Loop and Is Blocked by Inhibitors of Thiol-Disulfide Exchange

Abou-Jaoudé

Sureau

2007

J Virol

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Hepatitis delta virus (HDV) particles are coated with the envelope proteins (large, middle, and small) of the hepatitis B virus (HBV). The large protein bears an infectivity determinant in its pre-S1 domain, whereas a second determinant has been proposed to map to the cysteine-rich antigenic loop (AGL) within the S domain of all three envelope proteins (G. Abou Jaoudé and C. Sureau, J. Virol. 79:10460-10466, 2006). In this study, the AGL cysteines were substituted by serine or alanine, and the mutants were evaluated for their function at viral entry using HDV particles and susceptible HepaRG cells. Mutations of cysteines 121 to 149 were tolerant of the production of HDV virions. The mutations altered the structure and antigenicity of the conserved "a" determinant of the AGL, as measured by conformation-sensitive antibodies, and they created a block to infectivity. Substitution of Cys-90 or Cys-221, located outside of the AGL, had no impact on the "a" determinant or viral entry. Furthermore, infectivity was maintained when the AGL CxxC motif at position 121 to 124 was modified by single-amino-acid deletion or insertion, suggesting that cysteines 121 and 124 are not catalyzers of thiol/disulfide exchange. However, membrane-impermeable inhibitors of thiol/disulfide isomerazation demonstrated a dose-dependent inhibition of infection in an in vitro assay when applied to the virus prior to inoculation or during the virus-cell interaction period. Overall, the results demonstrate the essential role of the AGL cysteines at viral entry, and they establish a correlation between the cysteine disulfide network, the conformation of the "a" determinant, and infectivity.Hepatitis B virus (HBV) is responsible for acute and chronic liver disease that affects more than 400 million individuals worldwide (12). HBV is characterized by a very narrow host range that is likely to reflect a highly specific interaction between the viral envelope proteins and the receptor(s) at the surface of human hepatocytes. The mechanism of HBV entry is still poorly understood-the receptor remains unknownand only recently have determinants of infectivity been mapped to discrete domains within the amino acid sequence of the envelope proteins (2,4,16,24). HBV particles bear three sequence-related envelope proteins: the small protein (SHBsAg) consists of a 226-amino-acid-long transmembrane protein, the middle protein (M-HBsAg) includes the S domain and an additional N-terminal pre-S2 ectodomain that is 55 amino acids in length, and the large protein (L-HBsAg) comprises a N-terminal pre-S1 domain (109 amino acids) in addition to pre-S2 and S domains (20). Synthesis occurs at the endoplasmic reticulum (ER) membrane, but it leads almost exclusively to the secretion of empty subviral particles (SVPs). The assembly of mature HBV virions is a rare event that results from an interaction between the matrix domain of LHBsAg and the HBV nucleocapsid (6).The HBV envelope proteins also have the capacity to interact with the hepatitis delta virus (HDV) ribonucleoprote...

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Entry of Hepatitis Delta Virus Requires the Conserved Cysteine Residues of the Hepatitis B Virus Envelope Protein Antigenic Loop and Is Blocked by Inhibitors of Thiol-Disulfide Exchange

Abou-Jaoudé

Sureau

2007

J Virol

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“…A number of small deletions in the carboxyl part of CYL-I or that of the AGL were also detrimental for SVP production, but surprisingly, deletion of the entire AGL was tolerated for SVP secretion and seemed to affect only the mutant stability or its expression level (33). Mutational analysis of cysteine residues revealed that those located at positions 48, 65, and 69 in CYL-I and 107 in the AGL were essential for SVP secretion (30,31).…”

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Analysis of the Cytosolic Domains of the Hepatitis B Virus Envelope Proteins for Their Function in Viral Particle Assembly and Infectivity

Blanchet

Sureau

2006

J Virol

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The hepatitis B virus (HBV) envelope proteins have the ability to assemble three types of viral particles, (i) the empty subviral particles (SVPs), (ii) the mature HBV virions, and (iii) the hepatitis delta virus (HDV) particles, in cells that are coinfected with HBV and HDV. To gain insight into the function of the HBV envelope proteins in morphogenesis of HBV or HDV virions, we have investigated subdomains of the envelope proteins that have been shown or predicted to lie at the cytosolic face of the endoplasmic reticulum membrane during synthesis, a position prone to interaction with the inner core structure. These domains, referred to here as cytosolic loops I and II (CYL-I and -II, respectively), were subjected to mutagenesis. The mutations were introduced in the three HBV envelope proteins, designated small, middle, and large (S-HBsAg, M-HBsAg, and L-HBsAg, respectively). The mutants were expressed in HuH-7 cells to evaluate their capacity for self-assembly and formation of HBV or HDV virions when HBV nucleocapsid or HDV ribonucleoprotein, respectively, was provided. We found that SVP-competent CYL-I mutations between positions 23 and 78 of the S domain were permissive to HBV or HDV virion assembly. One mutation ( The hepatitis B virus (HBV) is characterized by a most peculiar budding mechanism, which is nucleocapsid independent and driven by its viral envelope proteins at a cellular internal membrane (17,35,36). The three envelope proteins, encoded by a unique open reading frame on the HBV genome, bear the hepatitis B virus surface antigen (HBsAg) and are referred to as large, middle, and small (L-HBsAg, M-HBsAg, and S-HBsAg, respectively) because they differ in the sizes of their respective amino-terminal ends (16). Interestingly, the driving force of the viral particle budding process is provided by the sole S-HBsAg protein (32), which is produced in abundance in infected cells. All three envelope proteins are synthesized at the endoplasmic reticulum (ER) membrane, where they aggregate through protein-protein interactions leading primarily to the secretion of empty S-HBsAg-coated subviral particles (SVPs) (16). It is only when L-HBsAg is present in the envelope protein aggregates at the ER membrane that the HBV nucleocapsid can be recruited in the budding complex and released as a mature virion (4). Owing to the overwhelming activity of S-HBsAg for self-assembly, in comparison to that of L-HBsAg, HBV virion formation occurs only on rare occasions.In addition to the formation of SVPs and mature HBV virions, the HBV envelope proteins can also assist in the assembly of hepatitis delta virus (HDV) particles (2, 49). HDV is an occasional satellite of HBV. Its genome consists of a circular single-stranded RNA molecule with only one open reading frame from which a protein is known to be translated (50). The latter is synthesized in two isoforms, the small and large hepatitis delta antigens (S-HDAg and L-HDAg, respectively). HDV RNA replicates without any assistance from the helper HBV, and it assembles with mul...

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“…Some previous studies observed that cysteine 69 was highly conserved and essential for HBsAg secretion from infected hepatocytes [25,26]. A stop codon mutation at this position may lead to the accumulation of the prematurely truncated form of HBsAg into the hepatocyte and may induce transactivation of cellular promoters, including those encoding oncogenic proteins.…”

Section: Discussionmentioning

confidence: 99%

Serological and molecular analysis on the relationships between type 2 diabetes mellitus and hepatitis B virus infection

Zhu

Wang

Yu³

et al. 2016

J Infect Dev Ctries

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Introduction: This study aimed to further analyze the associations between type 2 diabetes mellitus (T2DM) and hepatitis B virus (HBV) infection, and to investigate the relationships between T2DM and the mutations within the HBV major hydrophilic region (MHR). Methodology: In this cross-sectional study, 3,377 persons (338 T2DM patients and 3,039 non-diabetics) were randomly selected. HBsAg detection was performed by enzyme-linked immunosorbent assay. The HBV MHR was amplified, sequenced, and analyzed by nested PCR. Results: The seroprevalence of HBsAg was 21.30% in T2DM patients (72/338), which was significantly higher than in non-diabetics (15.53%). Compared to persons without T2DM, the proportion of T2DM patients positive for HBsAg was significantly elevated in males, people > 55 years (p = 0.039), and people with a body mass index (BMI) ≥ 24 kg/m 2 . Totally, 112 genotype B and 111 genotype C HBV sequences were isolated. No significant difference in HBV genotype distribution was observed between T2DM patients and non-diabetics. Compared to genotype C HBV-infected cases in non-diabetics, the amino acid substitution rates in the MHR were significantly higher in T2DM patients (p = 0.003). Moreover, seven HBV strains with stop codon mutations within the HBV S gene were identified: three from T2DM patients (5.45%) and four from non-diabetics (2.38%). Conclusions: In China, T2DM is significantly associated with chronic HBV infections and genotype C HBV MHR mutations. Being males, > 55 years of age, and ≥ 24 kg/m 2 of BMI are the risk factors of HBV infection in T2DM patients.

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Secretion and Antigenicity of Hepatitis B Virus Small Envelope Proteins Lacking Cysteines in the Major Antigenic Region

Cited by 94 publications

References 0 publications

Entry of Hepatitis Delta Virus Requires the Conserved Cysteine Residues of the Hepatitis B Virus Envelope Protein Antigenic Loop and Is Blocked by Inhibitors of Thiol-Disulfide Exchange

Entry of Hepatitis Delta Virus Requires the Conserved Cysteine Residues of the Hepatitis B Virus Envelope Protein Antigenic Loop and Is Blocked by Inhibitors of Thiol-Disulfide Exchange

Analysis of the Cytosolic Domains of the Hepatitis B Virus Envelope Proteins for Their Function in Viral Particle Assembly and Infectivity

Serological and molecular analysis on the relationships between type 2 diabetes mellitus and hepatitis B virus infection

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