Exposure of RNA Templates and Encapsidation of Spliced Viral RNA Are Influenced by the Arginine-Rich Domain of Human Hepatitis B Virus Core Antigen (HBcAg 165-173)

Pogam, Sophie Le; Chua, Pong Kian; Newman, Margaret A.; Shih, Chiaho

doi:10.1128/jvi.79.3.1871-1887.2005

Cited by 82 publications

(187 citation statements)

References 63 publications

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“…This phenotype is reminiscent of HBV core protein mutants bearing mutations within the arginine-rich carboxy terminus, which also contains three serine phosphorylation sites. 41,42 Therefore, it will be interesting to determine whether anti-hepadnaviral A3G activity may be mediated and/or modulated by HBV core protein phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

APOBEC-mediated interference with hepadnavirus production

et al. 2005

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APOBEC3G is a cellular cytidine deaminase displaying broad antiretroviral activity. Recently, it was shown that APOBEC3G can also suppress hepatitis B virus (HBV) production in human hepatoma cells. In the present study, we characterized the mechanisms of APO-BEC-mediated antiviral activity against HBV and related hepadnaviruses. We show that human APOBEC3G blocks HBV production in mammalian and nonmammalian cells and is active against duck HBV as well. Early steps of viral morphogenesis, including RNA and protein synthesis, binding of pregenomic RNA to core protein, and self-assembly of viral core protein, were unaffected. However, APOBEC3G rendered HBV core protein-associated full-length pregenomic RNA nuclease-sensitive. Ongoing reverse-transcription in capsids that had escaped the block in morphogenesis was not significantly inhibited. The antiviral effect was not modulated by abrogating or enhancing expression of the accessory HBV X protein, suggesting that HBV X protein does not represent a functional homologue to the HIV vif protein. Furthermore, human APOBEC3F but not rat APOBEC1 inhibited HBV DNA production. Viral RNA and low-level DNA produced in the presence of APOBEC3F or rat APOBEC1 occasionally displayed mutations, but the majority of clones were wild-type. In conclusion, APOBEC3G and APOBEC3F but not rat APOBEC1 can downregulate the production of replication-competent hepadnaviral nucleocapsids. In contrast to HIV and other retroviruses, however, APOBEC3G/3F-mediated editing of nucleic acids does not seem to represent an effective innate defense mechanism for hepadnaviruses. H epadnaviruses are a group of small enveloped DNA viruses with a narrow host range and a relative tropism for the liver. Hepatitis B virus (HBV), the prototypic member of the hepadnavirus family, is a major cause of liver disease worldwide, ranging from acute and chronic hepatitis to cirrhosis and hepatocellular carcinoma. 1,2 Other members of the family include the duck hepatitis B virus (DHBV) and the woodchuck hepatitis virus. 3,4 Hepadnaviral replication involves reverse-transcription of a pregenomic RNA (pgRNA) intermediate inside nucleocapsids, which are formed by 180 or 240 core protein subunits. Inside the capsid, the viral polymerase converts pgRNA into minus-strand DNA, which in turn is completed to a double-stranded, relaxed circular DNA molecule. 5,6 This life cycle places HBV into the large family of retroelements, which all require reverse-transcription of an RNA intermediate.Recently, a cellular defense mechanism targeting a wide range of retroviruses was identified. It was shown that the propagation of HIV-1 strains lacking the accessory protein Vif is suppressed in a number of nonpermissive cells and that this block was due to expression of the cytidine deaminase APOBEC3G (A3G). 7,8 Further studies revealed that A3G induces massive C3 U deamination of single stranded retroviral DNA, resulting in DNA degradation or lethal G3 A hypermutation. [9][10][11] Interestingly, A3G can also interfere with the HBV life c...

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Section: Discussionmentioning

confidence: 99%

APOBEC-mediated interference with hepadnavirus production

et al. 2005

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“…Upon nucleation around the RNA, the capsomers aggregate to form viruses of various T-number sizes with N segments inside and N 0 − N segments outside. It has been suggested that the outside fragments can be removed by nucleases (17,18). We focus on the subpopulation of singly encapsidated viral particles of a particular T-number.…”

Section: Clarification Of the Optimal Genome Lengthmentioning

confidence: 99%

Thermodynamic basis for the genome to capsid charge relationship in viral encapsidation

Ting

Wang

2011

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

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We establish an appropriate thermodynamic framework for determining the optimal genome length in electrostatically driven viral encapsidation. Importantly, our analysis includes the electrostatic potential due to the Donnan equilibrium, which arises from the semipermeable nature of the viral capsid, i.e., permeable to small mobile ions but impermeable to charged macromolecules. Because most macromolecules in the cellular milieu are negatively charged, the Donnan potential provides an additional driving force for genome encapsidation. In contrast to previous theoretical studies, we find that the optimal genome length is the result of combined effects from the electrostatic interactions of all charged species, the excluded volume and, to a very significant degree, the Donnan potential. In particular, the Donnan potential is essential for obtaining negatively overcharged viruses. The prevalence of overcharged viruses in nature may suggest an evolutionary preference for viruses to increase the amount of genome packaged by utilizing the Donnan potential (through increases in the capsid radius), rather than high charges on the capsid, so that structural stability of the capsid is maintained.polyelectrolyte | viral assembly T he most prevalent viruses in nature are single-stranded RNA viruses with the genetic material enclosed in icosahedral-shaped capsids made up of 60 T protein units, where the T-number is a small integer index. The protein units (capsomers) often contain highly basic peptide arms that extend into the capsid interior and, under physiological conditions, are positively charged. Electrostatic attraction provides the driving force for encapsidating the negatively charged RNA, which, in turn, helps overcome the electrostatic repulsion among the capsomers during the capsid assembly.In a series of classic experiments, Bancroft and coworkers (1, 2) demonstrated that certain viruses can encapsidate nonnative RNA and even generic polyanions. Dominance of the electrostatics as the driving force for viral assembly has led to the expectation of a simple relationship between the total capsid charge Q P and the genome charge Q R , as every nucleotide carries one unit of negative charge. Belyi and Muthukumar (3) compiled data for 19 wild type viruses from several viral families and found an apparent "universal" charge ratio of Q R ∕Q P ≈ 1.6, which they explained by combining the ground-state dominance approximation for polyelectrolyte binding to an oppositely charged polymer brush with the Manning condensation theory (4). The former predicts a 1∶1 charge ratio and the latter is used as a qualitative argument for the actual charge on the RNA being less than the nominal charge. Hu, et al. (5), however, assumed that the RNA winds around individual peptide arms and found that the viruses are most stable when the total contour length of the RNA is close to the total length of the peptide arms; this roughly gives a charge ratio of 2. In other works that ignore the peptide arms completely, there is additional disagreemen...

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“…The three-dimensional map reveals a protein architecture highly similar to that of HBcAg-149 [5][6][7]. The inner space of the HBcAg-154 particle is also nearly empty, indicating the minimum volume of RNA inside [10]. This is an outcome because its short C-terminal tail lacks enough arginines to package RNA.…”

Section: The Inner Structure Of Hbcag-154mentioning

confidence: 84%

“…As one kind of HBcAg particle constructed by the entire core protein, HBcAg-183 encapsidates large amounts of RNA in the capsid. In addition, HBcAg particles truncated between residues 154 and 183, such as HBcAg-164, 169, 171 and 173, also contain obvious RNA densities inside for their basic C-terminal tails which are longer than that of HBcAg-154 [10].…”

Section: The Inner Structure Of Hbcag-154mentioning

confidence: 99%

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Three-dimensional structure of the hepatitis B core antigen particle truncated at residue 154

Liu

Dai

et al. 2010

Sci. China Life Sci.

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The three-dimensional structure of recombinant hepatitis B core antigen (HBcAg) particles truncated at residue 154 (HBcAg-154) was determined to 7.8 Å resolution by cryo-electron microscopy (cryoEM) and computer reconstruction. The capsid of HBcAg-154 is mainly constituted by α-helical folds, highly similar to that of HBcAg-149. The C-terminal region between residues 155 and 183 of the core protein is more crucial to the encapsidation of RNA, and the short C-terminal tail of HBcAg-154 results in a nearly empty capsid. HBcAg-154 particle, capsid, RNA, cryoEM Citation:Liu S Y, He J, Li K P, et al.

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Exposure of RNA Templates and Encapsidation of Spliced Viral RNA Are Influenced by the Arginine-Rich Domain of Human Hepatitis B Virus Core Antigen (HBcAg 165-173)

Cited by 82 publications

References 63 publications

APOBEC-mediated interference with hepadnavirus production

APOBEC-mediated interference with hepadnavirus production

Thermodynamic basis for the genome to capsid charge relationship in viral encapsidation

Three-dimensional structure of the hepatitis B core antigen particle truncated at residue 154

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