Assembly and Release of Hepatitis B Virus

Selzer, Lisa; Zlotnick, Adam

doi:10.1101/cshperspect.a021394

Cited by 61 publications

(60 citation statements)

References 179 publications

(236 reference statements)

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“…Zlotnick and colleagues propose that the assembly of HBc could be taken as a target for novel antiviral drug design 1, 2 . Our work provides structural insights into HBc assembly, and may serve as a strategic guide for antiviral drug design.…”

Section: Discussionmentioning

confidence: 99%

Allosteric conformational changes of human HBV core protein transform its assembly

Liu

Fan

Wang

et al. 2017

Sci Rep

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Hepatitis B Virus core protein (HBc) has multiple roles in the viral lifecycle: viral assembly, compartment for reverse transcription, intracellular trafficking, and nuclear functions. HBc displays assembly polymorphism - it can assemble into icosahedral capsid and aberrant non-capsid structures. It has been hypothesized that the assembly polymorphism is due to allosteric conformational changes of HBc dimer, the smallest assembly unit, however, the mechanism governing the polymorphic assembly of the HBc dimer is still elusive. By using the experimental antiviral drug BAY 41-4109, we successfully transformed the HBc assembly from icosahedral capsid to helical tube. Structural analyses of HBc dimers from helical tubes, T = 4 icosahedral capsid, and sheet-like HBc ensemble revealed differences within the inter-dimer interface. Disruption of the HBc inter-dimer interface may likely promote the various assembly forms of HBc. Our work provides new structural insights into the HBV assembly mechanism and strategic guide for anti-HBV drug design.

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Section: Discussionmentioning

confidence: 99%

Allosteric conformational changes of human HBV core protein transform its assembly

Liu

Fan

Wang

et al. 2017

Sci Rep

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“…This selective ability of the nucleocapsid is thought to be due to destabilization of the nucleocapsid when the rcDNA synthesis approaches full length. These maturation-associated structural changes on the nucleocapsid will signal to the surface proteins for enveloping [19,20]. However, genome-free virions (enveloped nucleocapsids containing no RNA or DNA) are also secreted in a larger amount than complete virions [19,21].…”

Section: Virion Formation and Secretionmentioning

confidence: 99%

Hepatitis B core protein as a therapeutic target

Mak

Wong

Seto

et al. 2017

Expert Opinion on Therapeutic Targets

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Chronic hepatitis B virus (HBV) infection is difficult to cure, due to the presence of covalently-closed-circular DNA and virus-mediated blunting of host immune response. Existing therapies with nucleos(t)ide analogue or pegylated-interferon are not sufficient to achieve a high rate of HBV surface antigen seroclearance, a more desirable treatment outcome. Novel therapeutic agents targeting alternative viral replication steps are being developed. In this review, we will discuss the hepatitis B core antigen (HBcAg) as a therapeutic target. Areas covered: The basic structure and fundamental functions of HBcAg including nucleocapsid assembly, pre-genomic RNA encapsidation, reverse transcription, virion formation, cccDNA amplification, immune response regulation, and HBx protein interaction will be reviewed. Most of these are identified as therapeutic targets and tested in in vitro and in vivo studies, although clinical trials are scanty. Among the different components, the core protein allosteric modulators (CpAM) have been most widely investigated and appear promising in clinical trials. Expert opinion: The multiple and essential functions of HBcAg for HBV life cycle are important and attractive targets for HBV therapeutic interventions. Controlled trials involving CpAM are awaited. Apart from CpAM, drugs directed against different functions of HBcAg may be further explored to maximize the chance of cure.

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“…Hepatitis B Virus (HBV) is an enveloped virus with an icosahedral capsid. It is an important public health issue: 240 million people have chronic HBV infection and HBV contributes to 780,000 deaths each year . HBV also serves as a model system for studying capsid assembly .…”

Section: Introductionmentioning

confidence: 99%

“…In vitro HBV capsid self‐assembly has been studied using the 149‐residue assembly domain, Cp149, of the capsid protein. In solution, Cp149 is a dimer that assembles in response to increased ionic strength to predominantly form T = 4 (120 dimers) icosahedral capsids; depending on conditions, typically about 5% of capsids are 90‐mers with T = 3 icosahedral symmetry . During the HBV lifecycle, HBV capsid disassemble to release the viral genome and assemble to encapsidate the genome .…”

Section: Introductionmentioning

confidence: 99%

“…It is an important public health issue: 240 million people have chronic HBV infection and HBV contributes to 780,000 deaths each year. [1][2][3] HBV also serves as a model system for studying capsid assembly. [4][5][6][7][8][9][10] In vitro HBV capsid self-assembly has been studied using the 149residue assembly domain, Cp149, of the capsid protein.…”

Section: Introductionmentioning

confidence: 99%

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A molecular breadboard: Removal and replacement of subunits in a hepatitis B virus capsid

et al. 2017

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Hepatitis B virus (HBV) core protein is a model system for studying assembly and disassembly of icosahedral structures. Controlling disassembly will allow re-engineering the 120 subunit HBV capsid, making it a molecular breadboard. We examined removal of subunits from partially crosslinked capsids to form stable incomplete particles. To characterize incomplete capsids, we used two single molecule techniques, resistive-pulse sensing and charge detection mass spectrometry. We expected to find a binomial distribution of capsid fragments. Instead, we found a preponderance of 3 MDa complexes (90 subunits) and no fragments smaller than 3 MDa. We also found 90-mers in the disassembly of uncrosslinked HBV capsids. 90-mers seem to be a common pause point in disassembly reactions. Partly explaining this result, graph theory simulations have showed a threshold for capsid stability between 80 and 90 subunits. To test a molecular breadboard concept, we showed that missing subunits could be refilled resulting in chimeric, 120 subunit particles. This result may be a means of assembling unique capsids with functional decorations.

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Assembly and Release of Hepatitis B Virus

Cited by 61 publications

References 179 publications

Allosteric conformational changes of human HBV core protein transform its assembly

Allosteric conformational changes of human HBV core protein transform its assembly

Hepatitis B core protein as a therapeutic target

A molecular breadboard: Removal and replacement of subunits in a hepatitis B virus capsid

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