The Hepatitis B Virus Envelope Proteins: Molecular Gymnastics Throughout the Viral Life Cycle

Seitz, Stefan; Habjanič, Jelena; Schütz, Anne K.; Bartenschlager, Ralf

doi:10.1146/annurev-virology-092818-015508

Cited by 33 publications

(44 citation statements)

References 177 publications

(219 reference statements)

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“…1 B ), the capsid-forming core protein (Cp), the multifunctional polymerase, and an epigenetic regulator of HBV transcription, HBx (reviewed in refs. 4 – 6 , respectively). Cp ( Fig.…”

mentioning

confidence: 97%

A pocket-factor–triggered conformational switch in the hepatitis B virus capsid

Lecoq

Wang

Dujardin

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Viral hepatitis is growing into an epidemic illness, and it is urgent to neutralize the main culprit, hepatitis B virus (HBV), a small-enveloped retrotranscribing DNA virus. An intriguing observation in HB virion morphogenesis is that capsids with immature genomes are rarely enveloped and secreted. This prompted, in 1982, the postulate that a regulated conformation switch in the capsid triggers envelopment. Using solid-state NMR, we identified a stable alternative conformation of the capsid. The structural variations focus on the hydrophobic pocket of the core protein, a hot spot in capsid–envelope interactions. This structural switch is triggered by specific, high-affinity binding of a pocket factor. The conformational change induced by the binding is reminiscent of a maturation signal. This leads us to formulate the “synergistic double interaction” hypothesis, which explains the regulation of capsid envelopment and indicates a concept for therapeutic interference with HBV envelopment.

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“…1 B ), the capsid-forming core protein (Cp), the multifunctional polymerase, and an epigenetic regulator of HBV transcription, HBx (reviewed in refs. 4 – 6 , respectively). Cp ( Fig.…”

mentioning

confidence: 97%

A pocket-factor–triggered conformational switch in the hepatitis B virus capsid

Lecoq

Wang

Dujardin

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…However, the OBI-specific E2 mutations did not affect the secretion of HBV virions compared with pHBV1.3B/C ( p > 0.05) ( Figures 1C,D ). Actually, HBV virions and subviral particles (the main components of HBsAg) are produced and released in different pathways during HBV replication cycle ( Hu and Liu, 2017 ; Seitz et al, 2020 ), and not all the OBI-related mutations affect HBV DNA expression in vitro ( Garcia et al, 2009 ; Wu et al, 2010 ; Huang et al, 2012 ; Chen et al, 2016 ). Therefore, E2 mutations studied here strongly influenced the detection of HBsAg, but not virions.…”

Section: Discussionmentioning

confidence: 99%

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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“…Also complete enveloped virions egress from the cell via MVBs [ 65 ], dependent on the endosomal sorting complexes required for transport (ESCRT) machinery. Envelopment of matured nucleocapsids is mainly driven by interactions of the L protein, specifically a region near the C terminus of the PreS1 and the N terminus of the PreS2 domain (termed “matrix domain”), with still obscure signals on the capsid surface [ 66 ]. Capsid binding requires a cytoplasmic disposition of PreS1, equivalent to the virion interior, while cellular receptor recognition requires PreS1 on the virion surface.…”

Section: Functional Dynamics Of the Hbv Core Protein And Capsid In Virus Replicationmentioning

confidence: 99%

The Hepatitis B Virus Nucleocapsid—Dynamic Compartment for Infectious Virus Production and New Antiviral Target

2021

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Hepatitis B virus (HBV) is a small enveloped DNA virus which replicates its tiny 3.2 kb genome by reverse transcription inside an icosahedral nucleocapsid, formed by a single ~180 amino acid capsid, or core, protein (Cp). HBV causes chronic hepatitis B (CHB), a severe liver disease responsible for nearly a million deaths each year. Most of HBV’s only seven primary gene products are multifunctional. Though less obvious than for the multi-domain polymerase, P protein, this is equally crucial for Cp with its multiple roles in the viral life-cycle. Cp provides a stable genome container during extracellular phases, allows for directed intracellular genome transport and timely release from the capsid, and subsequent assembly of new nucleocapsids around P protein and the pregenomic (pg) RNA, forming a distinct compartment for reverse transcription. These opposing features are enabled by dynamic post-transcriptional modifications of Cp which result in dynamic structural alterations. Their perturbation by capsid assembly modulators (CAMs) is a promising new antiviral concept. CAMs inappropriately accelerate assembly and/or distort the capsid shell. We summarize the functional, biochemical, and structural dynamics of Cp, and discuss the therapeutic potential of CAMs based on clinical data. Presently, CAMs appear as a valuable addition but not a substitute for existing therapies. However, as part of rational combination therapies CAMs may bring the ambitious goal of a cure for CHB closer to reality.

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The Hepatitis B Virus Envelope Proteins: Molecular Gymnastics Throughout the Viral Life Cycle

Cited by 33 publications

References 177 publications

A pocket-factor–triggered conformational switch in the hepatitis B virus capsid

A pocket-factor–triggered conformational switch in the hepatitis B virus capsid

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

The Hepatitis B Virus Nucleocapsid—Dynamic Compartment for Infectious Virus Production and New Antiviral Target

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