RNA Editing and its Control in Hepatitis Delta Virus Replication

ABSTRACT Hepatitis delta virus (HDV) is a subviral human pathogen that uses specific RNA editing activity of the host to produce two essential forms of the sole viral protein, hepatitis delta antigen (HDAg). Editing at the amber/W site of HDV antigenomic RNA leads to the production of the longer form (HDAg-L), which is required for RNA packaging but which is a potent trans-dominant inhibitor of HDV RNA replication. Editing in infected cells is thought to be catalyzed by one or more of the cellular enzymes known as adenosine deaminases that act on RNA (ADARs). We examined the effects of increased ADAR1 and ADAR2 expression on HDV RNA editing and replication in transfected Huh7 cells. We found that both ADARs dramatically increased RNA editing, which was correlated with strong inhibition of HDV RNA replication. While increased HDAg-L production was the primary mechanism of inhibition, we observed at least two additional means by which ADARs can suppress HDV replication. High-level expression of both ADAR1 and ADAR2 led to extensive hyperediting at non-amber/W sites and subsequent production of HDAg variants that acted as trans-dominant inhibitors of HDV RNA replication. Moreover, we also observed weak inhibition of HDV RNA replication by mutated forms of ADARs defective for deaminase activity. Our results indicate that HDV requires highly regulated and selective editing and that the level of ADAR expression can play an important role: overexpression of ADARs inhibits HDV RNA replication and compromises virus viability.

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Resistance of Hepatitis Delta Virus Replication to Interferon- Treatment in Transfected Human Cells

The Journal of Infectious Diseases ◽

10.1093/infdis/166.5.1164 ◽

1992 ◽

Vol 166 (5) ◽

pp. 1164-1166 ◽

Cited By ~ 23

Author(s):

Y. Ilan ◽

A. Klein ◽

J. Taylor ◽

R. Tur-Kaspa

Keyword(s):

Virus Replication ◽

Hepatitis Delta Virus ◽

Human Cells ◽

Interferon Treatment ◽

Hepatitis Delta ◽

Delta Virus

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Effects of Conserved RNA Secondary Structures on Hepatitis Delta Virus Genotype I RNA Editing, Replication, and Virus Production

Journal of Virology ◽

10.1128/jvi.79.17.11187-11193.2005 ◽

2005 ◽

Vol 79 (17) ◽

pp. 11187-11193 ◽

Cited By ~ 13

Author(s):

Geetha C. Jayan ◽

John L. Casey

Keyword(s):

Secondary Structure ◽

Rna Editing ◽

Hepatitis Delta Virus ◽

Virus Production ◽

Rna Replication ◽

Base Pairing ◽

Genotype I ◽

Hepatitis Delta ◽

Hdv Genotype ◽

Delta Virus

ABSTRACT RNA editing of the hepatitis delta virus (HDV) antigenome at the amber/W site by the host RNA adenosine deaminase ADAR1 is a critical step in the HDV replication cycle. Editing is required for production of the viral protein hepatitis delta antigen long form (HDAg-L), which is necessary for viral particle production but can inhibit HDV RNA replication. The RNA secondary structural features in ADAR1 substrates are not completely defined, but base pairing in the 20-nucleotide (nt) region 3′ of editing sites is thought to be important. The 25-nt region 3′ of the HDV amber/W site in HDV genotype I RNA consists of a conserved secondary structure that is mostly base paired but also has asymmetric internal loops and single-base bulges. To understand the effect of this 3′ region on the HDV replication cycle, mutations that either increase or decrease base pairing in this region were created and the effects of these changes on amber/W site editing, RNA replication, and virus production were studied. Increased base pairing, particularly in the region 15 to 25 nt 3′ of the editing site, significantly increased editing; disruption of base pairing in this region had little effect. Increased editing resulted in a dramatic inhibition of HDV RNA synthesis, mostly due to excess HDAg-L production. Although virus production at early times was unaffected by this reduced RNA replication, at later times it was significantly reduced. Therefore, it appears that the conserved RNA secondary structure around the HDV genotype I amber/W site has been selected not for the highest editing efficiency but for optimal viral replication and secretion.

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