Among the animal viruses, hepatitis D virus (HDV) is currently the smallest known. The length of its single-stranded, negative polarity genome, which contains a single open reading frame encoding for delta antigen, contains only 1678 nucleotides. Despite the extreme simplicity of the HDV genome, it replicates and produces progeny even more actively than many RNA viruses. Therefore, many of the fundamental features of the life cycles of viruses can probably be embodied in the simple HDV. In this review, we focus on the role of delta antigen (HDAg). Viral delta antigen has been shown to be essential for viral replication, and its variant, the large delta antigen (L-HDAg), is required for viral assembly. The replication and assembly processes, however, take place in different compartments of infected cells. For example, HDV RNA enters the nucleus and even the nucleolus for replication and transcription. Recent studies have indicated that newly synthesized viral genomic RNA further moves to the cytoplasm. This scenario suggested that different stages of viral RNA replication might take place in several distinct subcellular compartments. As these stages of the HDV life cycle require the presence of viral delta antigen, the protein must be able to traffic to different but appropriate subcellular compartments to synchronize viral replication and assembly. The mechanisms by which the delta antigen orchestrates these complicated steps are the topics of this chapter.

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