Hepatitis delta virus (HDV), a satellite of hepatitis B virus (HBV), can increase the liver damage associated with HBV infections and the associated risk of progressing to hepatocellular carcinoma. The long-range goal of these studies is to understand the structure and replication of HDV.
Six aims are proposed. I. Initial studies have been made of the structure of natural and assembled virions and of the viral ribonucleoproteins isolated both from virions and from the nuclei of infected cells. It is proposed to (i) investigate for both virion and nuclear RNPs, the stoichiometry and specificity of the relevant interactions between the delta antigens and the HDV RNA, and (ii) extend the study to consider interactions between the delta antigens and hepadnavirus surface antigens which must occur in the cytoplasm during virion assembly. II. RNA-directed transcription of HDV RNA probably is thought to via redirection of the host RNA polymerase II. Initial studies have shown that nuclear extracts can transcribe HDV RNAs. It is proposed to (i) characterize the initiation sites of the nascent RNAs, (ii) assess sequences or structures needed for the initiation of RNA-directed RNA synthesis, (iii) investigate the role, if any, of delta antigens bound to template RNA, and (iv) compare and contrast transcription factors needed for RNA- relative to DNA-directed RNA synthesis by pol II. III. Initial studies have shown that inside an infected cell, a specific nucleotide on the genome of HDV RNA undergoes an essential post- transcriptional RNA-editing event. The reaction can be reconstituted in vitro using nuclear extracts. It is proposed to (i) define those features of the HDV genomic RNA that are needed for editing, (ii) investigate the mechanism by which the nucleotide is changed, and (iii) evaluate the hypothesis that the RNA modifying activity is related to an ubiquitous cellular enzyme, CTP synthetase. IV. HDV-associated pathogenesis will be studied with woodchucks and in a new animal system. Initial studies have shown that injection of HDV into the mouse leads to a single cycle of replication in hepatocytes. It is proposed to study initiation and clearance of HDV infections in (i) woodchucks and mice, in the absence of WHV, (ii) in mice with specific immune deficiencies, and (iii) in mice transgenic for hepadnavirus envelope proteins. V. The mouse can be infected with HDV by an injection into either the tail vein or the peritoneal cavity. To understand the mechanism of this infection it is proposed to (i) determine whether HDV can infect a susceptible non-liver cell as a step prior to ultimate infection and replication in hepatocytes, (ii) to find whether WHV can also infect the mouse, and if so, (iii) to examine coinfections with both HDV and WHV. VI. Further studies are needed to understand how the small form of the delta antigen supports genome replication. It is proposed (i) to test for essential cis-acting RNA sequences via specifically mutated and/or truncated forms of the HDV genome, and (ii) to pursue a newly-discovered property of both small and large forms of the delta antigen: stabilization of replicating, and non-replicating forms of the HDV genome.
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