HDV is a human pathogen typically associated with more damaging HBV infections of the liver. The long-range goal is to understand the novel mechanism of HDV replication, focusing on features not so far known to occur during the replication of other animal viruses.
Four aims are proposed: I. RNA synthesis in vitro: Surprisingly nuclear extracts from normal human liver cells transcribe both genomic and anti-genomic HDV RNAs. To characterize this unusual RNA-directed synthesis by host enzymes, nuclear extracts will be prepared, HDV RNAs added, and studies made of the assembly of transcription complexes, initiation of transcription, and synthesis of full-length or longer transcripts. RNA sequences or structures needed for initiation of RNA-directed synthesis will be assessed, and also the effects, if any, of purified small delta protein. II. RNA synthesis in vivo: Genome replication can be initiated by transfecting cells with in vitro assembled RNP complexes, made of HDV RNAs and recombinant delta proteins. This strategy mimics natural infections but does not require primary hepatocytes (the only cells known to express the virus receptor). Altering components of the RNP will determine the requirements of both RNA and protein, including an examination of the roles of delta proteins in the initiation of infection. 5'-RACE procedures will map putative transcription initiation sites help determine the consequences of altering RNA sequence and structure in the vicinity of such sites. III. 5'-Capping and nuclear export of mRNA transcripts in vivo: Studies will focus on whether natural HDV mRNA has a cap structure and a cis-acting nuclear export signal, and will help understand nuclear retention of large HDV RNAs. IV. Post-translational modifications of delta proteins: Large delta protein can be phosphorylated and is the only protein, from any virus, known to be farnesylated. Experiments will address an apparent linkages of these two modifications as well as their roles in replication. In summary, studies proposed in four specific aims will provide information on unique aspects of the HDV life cycle and, because HDV is possibly more dependent on host functions than any other animal virus, information on the host machinery, such as how the host pol II is redirected to copy RNA templates and how post-translational modifications can be subverted by viral proteins.
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