Recent Developments in Hepatitis Delta Virus Research

Lazinski, David W.; Taylor, John M.

doi:10.1016/s0065-3527(08)60049-4

Cited by 33 publications

(23 citation statements)

References 106 publications

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“…Prehybridization was performed with shaking at 55°C in NorthernMax PreHyb/Hyb buffer (Ambion) for approximately 2 h, and hybridization was performed overnight (16 to 18 h) with shaking, under the same temperature and buffer conditions. The riboprobe was made by in vitro transcription with the Ecl136II-linearized template pDL538 (18) in the presence of [ 32 P]UTP (Perkin-Elmer/ NEN).…”

Section: Vol 79 2005mentioning

confidence: 99%

Roles of Carboxyl-Terminal and Farnesylated Residues in the Functions of the Large Hepatitis Delta Antigen

O’Malley

Lazinski

2005

J Virol

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The large hepatitis delta antigen (HDAg-L) mediates hepatitis delta virus (HDV) assembly and inhibits HDV RNA replication. Farnesylation of the cysteine residue within the HDAg-L carboxyl terminus is required for both functions. Here, HDAg-L proteins from different HDV genotypes and genotype chimeric proteins were analyzed for their ability to incorporate into virus-like particles (VLPs). Observed differences in efficiency of VLP incorporation could be attributed to genotype-specific differences within the HDAg-L carboxyl terminus. Using a novel assay to quantify the extent of HDAg-L farnesylation, we found that genotype 3 HDAg-L was inefficiently farnesylated when expressed in the absence of the small hepatitis delta antigen (HDAg-S). However, as the intracellular ratio of HDAg-S to HDAg-L was increased, so too was the extent of HDAg-L farnesylation for all three genotypes. Single point mutations within the carboxyl terminus of HDAg-L were screened, and three mutants that severely inhibited assembly without affecting farnesylation were identified. The observed assembly defects persisted under conditions where the mutants were known to have access to the site of VLP assembly. Therefore, the corresponding residues within the wild-type protein are likely required for direct interaction with viral envelope proteins. Finally, it was observed that when HDAg-S was artificially myristoylated, it could efficiently inhibit HDV RNA replication. Hence, a general association with membranes enables HDAg to inhibit replication. In contrast, although myristoylated HDAg-S was incorporated into VLPs far more efficiently than HDAg-S or nonfarnesylated HDAg-L, it was incorporated far less efficiently than wild-type HDAg-L; thus, farnesylation was required for efficient assembly.Hepatitis delta virus (HDV) is a subviral agent that possesses a closed circular single-stranded RNA genome of approximately 1.7 kilobases (27, 28). Due to extensive internal complementarity, the HDV genome assumes a partially double-stranded unbranched rod-like structure (5, 16). HDV is a satellite of hepatitis B virus (HBV) and requires the HBV envelope proteins, or surface antigens (HBsAg), for virion assembly (28). HDV virions possess an inner core composed of HDV RNPs and an outer envelope composed of host lipids and HBsAg proteins. HDV encodes two core proteins, the small and large hepatitis delta antigens (HDAg-S and HDAg-L), from a single coding sequence (33). HDAg-S is expressed early during infection and is required for HDV RNA replication (15). HDAg-L is produced later during infection, inhibits HDV RNA replication in a potent trans-dominant manner, and is required for HDV assembly through its interaction with HBsAg (8, 9, 12). In addition, HDAg-L can also be incorporated into the so-called empty particles derived from HBsAg-S, giving rise to virus-like particles (VLPs) devoid of HDV or HBV nucleic acids (32).HDAg-L expression occurs after a host-mediated RNA editing event causes mutation of the HDAg-S UAG (amber) stop codon to a UGG (tryptophan)...

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Section: Vol 79 2005mentioning

confidence: 99%

Roles of Carboxyl-Terminal and Farnesylated Residues in the Functions of the Large Hepatitis Delta Antigen

O’Malley

Lazinski

2005

J Virol

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“…For example, while the small delta antigen promotes HDV genome replication, the large delta antigen is a potent transdominant inhibitor (11)(12)(13). The two isoforms also have differences in their ability to transactivate heterologous genes (14,15).…”

Section: Introductionmentioning

confidence: 99%

In vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus

Bordier¹,

Ohkanda²,

Liu³

et al. 2003

J. Clin. Invest.

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“…Its genome consists of a single-stranded negative-sense circular RNA of approximately 1.7 kb that is 70% self-complementary and that can form a rod-like structure (11). HDV replicates via a rolling-circle mechanism in which a host-encoded RNA-directed RNA polymerase transcribes the circular genome to generate multimeric products (12). Within each monomeric unit of the multimer, a ribozyme self-cleaves, thereby releasing unitlength linear RNAs (12).…”

mentioning

confidence: 99%

“…HDV replicates via a rolling-circle mechanism in which a host-encoded RNA-directed RNA polymerase transcribes the circular genome to generate multimeric products (12). Within each monomeric unit of the multimer, a ribozyme self-cleaves, thereby releasing unitlength linear RNAs (12). The two termini of the linear monomer are joined by a host-encoded RNA ligase to create a circular replication intermediate referred to as the antigenome (23).…”

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confidence: 99%

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Hepatitis Delta Virus Minimal Substrates Competent for Editing by ADAR1 and ADAR2

Sato

Wong

Lazinski

2001

J Virol

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A host-mediated RNA-editing event allows hepatitis delta virus (HDV) to express two essential proteins, the small delta antigen (HDAg-S) and the large delta antigen (HDAg-L), from a single open reading frame. One or several members of the ADAR (adenosine deaminases that act on RNA) family are thought to convert the adenosine to an inosine (I) within the HDAg-S amber codon in antigenomic RNA. As a consequence of replication, the UIG codon is converted to a UGG (tryptophan [W]) codon in the resulting HDAg-L message. Here, we used a novel reporter system to monitor the editing of the HDV amber/W site in the absence of replication. In cultured cells, we observed that both human ADAR1 (hADAR1) and hADAR2 were capable of editing the amber/W site with comparable efficiencies. We also defined the minimal HDV substrate required for hADAR1-and hADAR2-mediated editing. Only 24 nucleotides from the amber/W site were sufficient to enable efficient editing by hADAR1. Hence, the HDV amber/W site represents the smallest ADAR substrate yet identified. In contrast, the minimal substrate competent for hADAR2-mediated editing contained 66 nucleotides.

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Recent Developments in Hepatitis Delta Virus Research

Cited by 33 publications

References 106 publications

Roles of Carboxyl-Terminal and Farnesylated Residues in the Functions of the Large Hepatitis Delta Antigen

Roles of Carboxyl-Terminal and Farnesylated Residues in the Functions of the Large Hepatitis Delta Antigen

In vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus

Hepatitis Delta Virus Minimal Substrates Competent for Editing by ADAR1 and ADAR2

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