Treatment of chronic delta hepatitis with α-2 recombinant interferon

Rizzetto, Mario; Rosina, F.; Saracco, Giorgio Maria; Bellando, P; Actis, Giovanni C; Bonino, Ferruccio; Smedile, Antonina; Trinchero, P.; Sansalvadore, F; Pintus, C.; Dianzani, F.; Verme, G

doi:10.1016/s0168-8278(86)80125-8

Cited by 43 publications

(18 citation statements)

References 7 publications

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“…For hepatitis D patients, interferon has been used for treatment. Unfortunately, the success rate was very low, and post-treatment relapse is common (49,50). How HDV escapes from interferon activity remains unknown.…”

Section: Discussionmentioning

confidence: 99%

The Double-stranded RNA-activated Kinase, PKR, Can Phosphorylate Hepatitis D Virus Small Delta Antigen at Functional Serine and Threonine Residues

Chen

Tsay

et al. 2002

Journal of Biological Chemistry

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Hepatitis D virus (HDV) encodes two proteins, the 24-kDa small delta antigen (S-HDAg) and 27-kDa large delta antigen (L-HDAg) in its single open reading frame. Both of them had been identified as nuclear phosphoproteins. Moreover, the phosphorylated form of S-HDAg was shown to be important for HDV replication. However, the kinase responsible for S-HDAg phosphorylation remains unknown. Therefore, we employed an ingel kinase assay to search candidate kinases and indeed identified a kinase with a molecular mass of about 68 kDa. Much evidence demonstrated this kinase to be the double-stranded RNA-activated kinase, PKR. The immunoprecipitated endogenous PKR was sufficient to catalyze S-HDAg phosphorylation, and the kinase activity disappeared in the PKR-depleted cell lysate. The S-HDAg and PKR could be co-immunoprecipitated together, and both of them co-located in the nucleolus. The LC/MS/MS analysis revealed that the serine 177, serine 180, and threonine 182 of S-HDAg were phosphorylated by PKR in vitro. This result was consistent with previous phosphoamino acid analysis indicating that serine and threonine were phosphorylation targets in S-HDAg. Furthermore, serine 177 was also shown to be the predominant phosphorylation site for S-HDAg purified the from cell line. In dominant negative PKR-transfected cells, the level of phosphorylated S-HDAg was suppressed, but replication of HDV was enhanced. Other than human immunodeficiency virus type 1 trans-activating protein (Tat), S-HDAg is another viral protein phosphorylated by PKR that may regulates HDV replication and viral response to interferon therapy.Hepatitis delta virus (HDV) 1 is the satellite virus of hepatitis B virus (1, 2), since it requires the hepatitis B virus envelope surface antigen (HBsAg) for viral particle assembly (3-5). Upon superinfection or co-infection with hepatitis B virus, HDV may cause fulminant hepatitis and progressive chronic liver disease (6, 7). The genome of HDV is a circular, single-stranded RNA that resembles the structure of plant viroid (8, 9). HDV contains the ribozyme domains for self-cleavage and self-ligation in both genomic and antigenomic strands of RNA (10, 11). Similar to viroid replication, HDV undergoes a double rolling circle scheme. However, different from viroids, HDV encodes two proteins translated from the same mRNA, small delta antigen (S-HDAg) and large delta antigen (L-HDAg) (12, 13). This viral mRNA is responsible for S-HDAg production. LHDAg is translated from the same open reading frame through a specific RNA editing process by which the UAG amber termination codon of S-HDAg was converted to UGG tryptophan codon and an additional 19 amino acids were made (14,15). This adenosine-to-inosine RNA editing is catalyzed by doublestranded RNA adenosine deaminase (15, 16). Although both forms of delta antigens (HDAg) share an identical N-terminal 194 amino acids, their functions are quite different. The SHDAg is essential for viral replication, whereas L-HDAg inhibits replication and is required for viral assembly (17-19...

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Section: Discussionmentioning

confidence: 99%

The Double-stranded RNA-activated Kinase, PKR, Can Phosphorylate Hepatitis D Virus Small Delta Antigen at Functional Serine and Threonine Residues

Chen

Tsay

et al. 2002

Journal of Biological Chemistry

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“…The HBeAg-positive patients have significantly higher HBsAg levels than HBeAgnegative patients. 26 Although severe HDV occurs in patients who are HBeAg-positive, 27,28 the percentage of liver transplant recipients is higher in HBeAgnegative patients. In our patients, the anti-HBe antibody positive rate was 100%.…”

Section: Discussionmentioning

confidence: 99%

Untitled

2015

Exp Clin Transplant

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“…HDAg in the liver and serum diminishes or disap pears, HDV RNA in serum disappears and aspartate aminotransferase levels drop. After stopping treatment HDV replication usually reappears with elevation of serum aspartate aminotransferase levels [132,133] …”

Section: Treatment Of Chronic Hepatitis Dmentioning

confidence: 99%