Morphogenesis of hepatitis B virus and its subviral envelope particles

Patient, Romuald; Hourioux, Christophe; Roingeard, Philippe

doi:10.1111/j.1462-5822.2009.01363.x

Cited by 134 publications

(140 citation statements)

References 70 publications

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“…s-HBsAg has an N-terminal transmembrane domain 1 (TM-I) that is not removed, a cytoplasmic domain, a TM-II domain followed by an extracellular loop with a single N-linked glycosylation site, and two further TM domains near the C terminus. Expression of s-HBsAg in mammalian cells results in formation of virus-like, lipid-associated particles that are N-glycosylated and secreted (30). However, in yeast, s-HBsAg accumulates in the endoplasmic reticulum (ER), and virus-like particles form after the cell wall is broken and cells are treated with detergents (31).…”

Section: Discussionmentioning

confidence: 99%

Unexpected fold in the circumsporozoite protein target of malaria vaccines

Doud

Koksal

et al. 2012

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

102

157

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Circumsporozoite (CS) protein is the major surface component of Plasmodium falciparum sporozoites and is essential for host cell invasion. A vaccine containing tandem repeats, region III, and thrombospondin type-I repeat (TSR) of CS is efficacious in phase III trials but gives only a 35% reduction in severe malaria in the first year postimmunization. We solved crystal structures showing that region III and TSR fold into a single unit, an "αTSR" domain. The αTSR domain possesses a hydrophobic pocket and core, missing in TSR domains. CS binds heparin, but αTSR does not. Interestingly, polymorphic T-cell epitopes map to specialized αTSR regions. The N and C termini are unexpectedly close, providing clues for sporozoite sheath organization. Elucidation of a unique structure of a domain within CS enables rational design of next-generation subunit vaccines and functional and medicinal chemical investigation of the conserved hydrophobic pocket.

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Section: Discussionmentioning

confidence: 99%

Unexpected fold in the circumsporozoite protein target of malaria vaccines

Doud

Koksal

et al. 2012

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

102

157

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“…Recent work demonstrates that HBV particles are released by a different pathway. The release of virions occurs ESCRT (endosomal sorting complex required for transport)-dependently via multivesicular bodies (MVBs) (8,10,11). ESCRT-MVB complex is mainly composed of ESCRT-I, .…”

Section: Importancementioning

confidence: 99%

“…They are transported to the ER-Golgi intermediate compartment (ERGIC) and released by the general secretory pathway (8,9). They are efficiently secreted and do not accumulate within the hepatocytes.…”

mentioning

confidence: 99%

Subviral Hepatitis B Virus Filaments, like Infectious Viral Particles, Are Released via Multivesicular Bodies

Jiang

Himmelsbach

Ren

et al. 2016

J Virol

123

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In addition to infectious viral particles, hepatitis B virus-replicating cells secrete large amounts of subviral particles assembled by the surface proteins, but lacking any capsid and genome. Subviral particles form spheres (22-nm particles) and filaments. Filaments contain a much larger amount of the large surface protein (LHBs) compared to spheres. Spheres are released via the constitutive secretory pathway, while viral particles are ESCRT-dependently released via multivesicular bodies (MVBs). The interaction of virions with the ESCRT machinery is mediated by ␣-taxilin that connects the viral surface protein LHBs with the ESCRT component tsg101. Since filaments in contrast to spheres contain a significant amount of LHBs, it is unclear whether filaments are released like spheres or like virions. To study the release of subviral particles in the absence of virion formation, a core-deficient HBV mutant was generated. Confocal microscopy, immune electron microscopy of ultrathin sections and isolation of MVBs revealed that filaments enter MVBs. Inhibition of MVB biogenesis by the small-molecule inhibitor U18666A or inhibition of ESCRT functionality by coexpression of transdominant negative mutants (Vps4A, Vps4B, and CHMP3) abolishes the release of filaments while the secretion of spheres is not affected. These data indicate that in contrast to spheres which are secreted via the secretory pathway, filaments are released via ESCRT/MVB pathway like infectious viral particles. IMPORTANCEThis study revises the current model describing the release of subviral particles by showing that in contrast to spheres, which are secreted via the secretory pathway, filaments are released via the ESCRT/MVB pathway like infectious viral particles. These data significantly contribute to a better understanding of the viral morphogenesis and might be helpful for the design of novel antiviral strategies.T he human hepatitis B virus (HBV) is a spherical particle, 42 nm in diameter, consisting of an outer envelope and an inner icosahedral nucleocapsid. The nucleocapsid is formed by the core protein and harbors the viral genomic DNA. The HBV genome encodes at least four different open reading frames, coding for the viral polymerase, the core and the e antigen (HBcAg and HBeAg), the regulatory X protein (HBx), and the three different surface proteins (HBsAg): the large HBV surface protein (LHBs), the middle surface protein (MHBs) and the small surface protein (SHBs) (1). LHBs encompasses the PreS1 domain, the PreS2 domain, and the S domain, MHBs consists of the PreS2 and the S domain, and SHBs contains the S domain. These surface proteins are not only constitutive components of the envelope of viral particles but also assemble to capsid-free subviral particles lacking any viral genome having the shape of spheres and filaments (2) that are secreted in 1,000-to 100,000-fold excess relative to infectious viral particles. SHBs, the predominant part of these subviral particles, can assemble to 22-nm spherical particles. The incorporation ...

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“…As was shown previously, the expression of HBV pgRNA by the pSFV1 expression vector allows the synthesis of all HBV structural proteins , including HBc and three variants of envelope (HBs) proteins: S, M, and L. As the HBc capsid interacts with HBs protein residing on the membrane of the ER to form the HBV virion (Patient et al, 2009), it is possible that HBc retention in the cell cytoplasm at the middle p.i. time was influenced by capsid interaction with envelope proteins in this experimental system.…”

Section: Intracellular Distribution Of Hbc and Hbs Proteins Expressedmentioning

confidence: 99%

A Semliki Forest virus expression system as a model for investigating the nuclear import and export of hepatitis B virus nucleocapsid protein

Zajakina¹,

Brüvere²,

Kozlovska³

2014

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Summary. -HBV core protein (HBc), the major component of nucleocapsid is known to have an essential role in the virus life cycle as the transporter of virus genome to the host nucleus; however, molecular details of the intracellular transport of HBc remain unknown. In this study, we investigated the intracellular distribution of the HBc protein resulting from Semliki Forest virus (SFV)-driven HBc gene and HBV RNA pregenome (pgRNA) expression in BHK-21 cells. Fluorescent confocal microscopy revealed extensive HBc protein synthesis in the cytoplasm 12 hr post infection (p.i.) with recombinant pSFV1/HBc or pSFV1/HBVpgRNA viruses. Twenty-four hr p.i., the HBc protein showed asymmetric, predominantly nuclear localization in most cells. However, 42 hr p.i., the number of cells containing intranuclear HBc protein, dramatically decreased to ~ 5%, while cytoplasmic HBc protein was detected in all cells. Remarkably, 24 hr p.i. with pSFV1/HBVpgRNA virus, cytoplasmic HBc protein colocalized with HBs protein. We conclude that a HBs-HBc interaction partially prevents the transport of HBc from the cytoplasm to nucleus. The SFV-driven system can be used for identification of new factors involved in the HBV nuclear import and export.

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Morphogenesis of hepatitis B virus and its subviral envelope particles

Cited by 134 publications

References 70 publications

Unexpected fold in the circumsporozoite protein target of malaria vaccines

Unexpected fold in the circumsporozoite protein target of malaria vaccines

Subviral Hepatitis B Virus Filaments, like Infectious Viral Particles, Are Released via Multivesicular Bodies

A Semliki Forest virus expression system as a model for investigating the nuclear import and export of hepatitis B virus nucleocapsid protein

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