Other reviews on the topic of hepatitis delta virus (HDV) RNA structure and replication have been previously published (Cunha et al. 2003; Gerin et al. 2001; Taylor 2003, 2004). Moreover this volume contains current reviews on other aspects of HDV infection, in addition to one chapter on HDV replication (see chapter by T.B. Macnaughton and M.M.C. Lai, this volume). The objective of this chapter therefore will be to not only review information regarding HDV genome structure and replication, but also to consider what might be new insights and to point to questions yet to be solved.

Over the years HDV has provoked interest because of the many unique features associated with its replication including RNA-directed transcription by a host enzyme, ribozyme domains, and essential RNA editing. It has also been associated with a deceptive simplicity: a very small genome encoding only one or two viral proteins to account for, and a rolling-circle model of replication that seems plausible. However, as described in this chapter, we are becoming aware of a greater complexity associated with the replication of this apparently simple virus.

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