Structure and Replication of Hepatitis Delta Virus RNA

Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA [email protected]

1 Introduction 2

2 RNAs and Ribonucleoproteins 2

2.1 Genome and Antigenome 2

2.2 mRNA 3

2.3 Other HDV RNAs 4

2.4 RNA Structure 5

2.5 Ribonucleoproteins 6

3 RNA Replication 7

3.1 Roles of Delta Proteins 7

3.1.1 The Essential Small Delta Protein 7

3.1.2 Other Forms of Delta Protein 7

3.1.3 Replication with an Unchanging Separate Source of Small Delta Protein. . 8

3.2 Enzymology of RNA-Directed Transcription 8

3.3 Initiation of Replication 9

3.4 Double Rolling-Circle Model 11

3.5 Template-Switching, Reconstitution, and Recombination 12

3.6 Inhibition of Replication 14

3.6.1 Resistance to Interferons 14

3.6.2 Sensitivity to Ribavirin 14

3.6.3 Sensitivity to siRNA 15

3.6.4 Resistance to Dicer 15

3.7 Cytopathic Effect of Replication 15

4 Evolution of the RNA Sequence 16

4.1 Accumulation of Changes 16

4.2 ADAR-Editing 17

4.3 Origin 17

5 Outlook 18

References 18

Abstract While this volume covers many different aspects of hepatitis delta virus (HDV) replication, the focus in this chapter is on studies of the structure and replication of the HDV RNA genome. An evaluation of such studies is not only an integral part of our understanding of HDV infections but it also sheds new light on some important aspects of cell biology, such as the fidelity of RNA transcription by a host RNA polymerase and on various forms of post-transcriptional RNA processing. Representations of the replication of the RNA genome are frequently simplified to a form of rolling-circle model, analogous to what have been described for plant viroids. One theme of this review is that such models, even after some revision, deceptively simplify the complexity of HDV replication and can fail to make clear major questions yet to be solved.

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