RNA Editing in Hepatitis Delta Virus

Department of Microbiology and Immunology, Georgetown University Medical

Center, Washington, DC, USA

[email protected]

1 Introduction 68

1.1 HDV Produces Two Forms of HDAg from the Same Gene 68

1.2 What Is RNA Editing? 69

1.3 Adenosine Deamination at the Amber/W Site in the HDV Antigenome .. 69

1.4 The Role of RNA Editing in the HDV Replication Cycle 70

2 Host Enzymes Required for HDV RNA Editing 72

3 Factors Affecting Substrate Selection 72

3.1 RNA Sequence and Structural Requirements for Editing 73

3.2 Variations in Amber/W Site Structures Among HDV Genotypes 75

4 Effects of Variations in Editing on HDV RNA Replication and Virus Production 77

4.1 Effects of Excessive Editing at the Amber/W Site 77

4.2 Effects of Diminished Editing at the Amber/W Site 78

5 Control of HDV RNA Editing 79

5.1 Restriction of Editing to the Amber/W Site 79

5.2 Regulation of Editing Levels 80

5.2.1 Effects of HDAg 81

5.2.2 Effects of RNA Structural Dynamics 82

5.2.3 Negative Feedback Regulation 82

6 Perspective 84

References 85

Abstract Hepatitis delta virus (HDV) relies heavily on host functions and on structural features of the viral RNA. A good example of this reliance is found in the process known as HDV RNA editing, which requires particular structural features in the HDV antigenome, and a host RNA editing enzyme, ADAR1. During replication, the adenosine at the amber/W site in the HDV antigenome is edited to inosine. As a result, the amber stop codon in the hepatitis delta antigen (HDAg) open reading frame is changed to a tryptophan codon and the reading frame is extended by 19 or 20 codons. Because these extra amino acids alter the functional properties of HDAg, this change serves a critical purpose in the HDV replication cycle. Analysis of the RNA secondary structures and regulation of editing in HDV genotypes I and III has indicated that although editing is essential for both genotypes, there are substantial differences. This review covers the mechanisms of RNA editing in the HDV replication cycle and the regulatory mechanisms by which HDV controls editing.

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