Hepatitis delta virus mutant: effect on RNA editing

Wu, Tsung–Teh; Bichko, V.; Ryu, Wang Shick; Lemon, Stanley M.; Taylor, John M.

doi:10.1128/jvi.69.11.7226-7231.1995

Cited by 26 publications

(16 citation statements)

References 27 publications

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“…[9][10][11][12][13] Previous mutagenesis studies have shown the effects of nucleotide substitutions or base pair mismatching in this region on RNA editing. 41,42 In this study, an examination of the nucleotide sequence surrounding the critical adenosine 1,012 of genotypes I and HDV shows that there are genotypic variations in both primary sequences and possible secondary structures (Fig. 7A).…”

Section: Efficiencies Of Rna Editing Between Genotypes I and Ii Hdvmentioning

confidence: 55%

Varied assembly and RNA editing efficiencies between genotypes I and II hepatitis D virus and their implications

Hsu¹,

Syu²,

Sheen

et al. 2002

Hepatology

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The mechanisms that link genotypes of hepatitis D virus (HDV) with clinical outcomes have not yet been elucidated. Genotypic variations are unevenly distributed along the sequences of hepatitis delta antigens (HDAgs). Of these variations, the packaging signal at the Cterminus has a divergence of 74% between genotypes I and II. In this report, we address the issue of whether these high variations between genotypes affect assembly efficiency of HDV particles and editing efficiency of RNA. Viral package systems of transfection with expression plasmids of hepatitis B surface antigen and HDAgs or whole genomes of HDV consistently indicate that the package efficiency of genotype I HDV is higher than that of genotype II. Segment swapping of large-form HDAg indicates that the C-terminal 19-residue region plays a key role for the varied assembly efficiencies. Also, the editing efficiency of genotype I HDV is higher than that of genotype II. The nucleotide and structural changes surrounding the editing site may explain why genotype II HDV has a low RNA editing efficiency. The findings of in vitro assembly systems were further supported by the observations that patients infected with genotype II had significantly lower alanine transaminase (ALT) levels, more favorable outcomes (P < .05), and a trend to have lower serum HDV RNA levels as compared with those infected with genotype I HDV (P ‫؍‬ .094). Coinfection or superinfection of HBV with HDV may cause severe liver diseases in humans. 3-8 An HDV viral particle is composed of HBsAg, a single-strand circular 1.7-kb RNA, and 2 forms of hepatitis delta antigen (HDAg). 9,10 HDV replicates through a rolling-circle mechanism involving RNA-directed RNA synthesis of genomic RNA and its complement, antigenomic RNA. 9,10 During the replication cycle of HDV, RNA editing at adenosine 1,012 (amber/W site) in antigenomic RNA allows the synthesis of 2 forms of HDAg from a single open reading frame. 11-13 The largeform HDAg (HDAg-L) is identical to the small-form (HDAg-S) except for a 19-amino acid extension at the C-terminus. 9,10 The Cxxx motif in this C-terminal extension is essential for isoprenylation, a function required for the package of HDV. 14 Both HDAg-S and HDAg-L form oligomers 15 and interact with viral RNA. 16,17 HDAg-L plays a crucial role in the assembly of HDV and suppresses viral replication, 18-20 whereas HDAg-S plays the opposite role in transactivating the replication of HDV RNA. 21,22 In addition to fulminant hepatitis or rapidly progressive chronic active hepatitis, HDV infection may also run a subclinical course. 8,23 Factors associated with different outcomes are still unclear. Persistent replication of HDV and/or HBV have been reported to be associated with active liver diseases. 8,24 There are 3 genotypes of HDV. 25 Genotype III HDV, prevalent in northern South America, has been associated with a severe form of hepatitis. 25 Whereas genotype II HDV, isolated from Japan and Taiwan, 26-29 is more frequently associated with a less aggressive disease as compared wi...

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Section: Efficiencies Of Rna Editing Between Genotypes I and Ii Hdvmentioning

confidence: 55%

Varied assembly and RNA editing efficiencies between genotypes I and II hepatitis D virus and their implications

Hsu¹,

Syu²,

Sheen

et al. 2002

Hepatology

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“…1, encoding the 195-amino-acid short form of HDAg (‫ץ‬Ag-S). When RNA editing occurs (3,5,22,37), a new frame is created; this frame has the same start codon but its stop codon is 57 bases further downstream, resulting in synthesis of the large form of HDAg (‫ץ‬Ag-L), with 214 amino acids. Both the Somalian and the Ethiopian isolates contain presumed RNA editing sites (Fig.…”

Section: Resultsmentioning

confidence: 99%

Phylogenetic analysis of hepatitis D viruses indicating a new genotype I subgroup among African isolates

1996

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The complete nucleotide sequence and genomic organization are described for the first time for two African HDV isolates. Phylogenetic analysis showed all the African isolates to be intrarelated and to form a novel group within HDV genotype I; the suggested designation for this group is IC. The genetic distance to previously described type I isolates was about 0.15. The HDV genotype I isolates (total of 22 examined) phylogenetically formed three clusters, each of them corresponding to certain geographic regions; the "western" group consisted of six HDV isolates from western Europe and the United States plus one from Kuwait; the "eastern" group consisted of two isolates from Moldavia and one each from Bulgaria, Nauru, mainland China, and Taiwan; and the "African-Middle East" group consisted of six HDV isolates from Ethiopia and one each from Somalia, Jordan, and Lebanon.

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“…Huh7, a line of human hepatoma cells (25), was seeded in plastic 35-mm-diameter tissue culture wells (Costar). Lipofectamine (Bethesda Research Laboratories) was used to transfect subconfluent cells in the presence of Opti-MEM (Bethesda Research Laboratories), as recommended by the manufacturer (13) but with modifications, as previously described (37). ␦Ag-L empty particles.…”

Section: Methodsmentioning

confidence: 99%

Phosphorylation of the hepatitis delta virus antigens

Bichko

Barik

Taylor

1997

J Virol

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We used two-dimensional electrophoresis (nonequilibrium pH gradient electrophoresis followed by sodium dodecyl sulfate-10% polyacrylamide gel electrophoresis) coupled with 32 P labeling and immunoblotting detection with 125 I-protein A to detect and quantitate phosphorylation of the large and small forms of the delta antigen (␦Ag-L and ␦Ag-S, respectively). Analysis of ␦Ag species from the serum and liver of an infected woodchuck as well as ␦Ag species expressed in and secreted from transfected Huh7 cells revealed the following. (i) No detectable phosphorylation of ␦Ag-S occurred. (ii) In virions from the serum of an infected animal and in the particles secreted from cotransfected cells, none of the ␦Ag-L was phosphorylated. (iii) Only in the infected liver and in transfected cells was any phosphorylation detected; it corresponded to a monophosphorylated form of ␦Ag-L. Given these results, we carried out serine-to-alanine mutagenesis of the ␦Ag-L to determine whether the monophosphorylation was predominantly at a specific site on the unique 19-amino-acid (aa) extension. We mutated each of the two serines, aa 207 and 210, on this extension and also the serine at aa 177. These three mutations had no significant effect on phosphorylation. In contrast, mutagenesis to alanine of the cysteine at aa 211, which normally acts as the acceptor for farnesylation, completely inhibited phosphorylation. Our interpretation is that the site(s) of phosphorylation is probably not in the 19-aa extension unique to ␦Ag-L and that phosphorylation of ␦Ag-L may depend upon prior farnesylation. The possible significance of the intracellular phosphorylated forms of ␦Ag-L is discussed.

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Hepatitis delta virus mutant: effect on RNA editing

Cited by 26 publications

References 27 publications

Varied assembly and RNA editing efficiencies between genotypes I and II hepatitis D virus and their implications

Varied assembly and RNA editing efficiencies between genotypes I and II hepatitis D virus and their implications

Phylogenetic analysis of hepatitis D viruses indicating a new genotype I subgroup among African isolates

Phosphorylation of the hepatitis delta virus antigens

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