Genetic and Phenotypic Diversity of Hepatitits Delta Vi Rus

Hepatitis delta virus (HDV) is a human pathogen that consists of a 1.7-kb negative-sense RNA genome. HDV is unique among animal viruses in that it has an unbranched rod-like circular RNA genome with autocatalytic cleavage activity and a replication strategy that redirects host RNA polymerase(s) to transcribe viral RNA. However, similar to many RNA viruses, HDV exhibits high genetic heterogeneity. Three known mechanisms for generating genetic diversity in HDV are host RNA polymerase-involved incorporation errors and homologous RNA recombination as well as host adenosine deaminase ADAR1-catalyzed amber/W RNA editing. RNA recombination is performed by a host polymerase-driven and viral RNA structure-promoted template-switching mechanism. HDV-1, 2, and 4 are found in Taiwan, where HDV-2 is predominant and mixed-clade infections are reported. Using the newly constructed HDV-2 cDNA clones, whole-genome recombination maps involving HDV-2 sequences will be established. Based on the information provided in the maps, the underlined molecular mechanism for HDV RNA recombination and the biological significances of HDV recombinant genomes and chimeric viral protein, delta antigen (HDAg), will be investigated. There are two forms of HDAg; the small one supports viral RNA replication while the large one, which is produced via amber/W editing, is required for packaging. Whole-genome sequence analyses of cultured cells transfected with a HDV sequence indicated that, in addition to the well-documented amber/W editing, three potential RNA editing events occurring at nt 1375 (in HDAg open reading frame and referred to as R/Q RNA editing) and nt 218-219 were identified. The biological significance and the crucial trans factors/c/s-elements in the regulation of the newly identified RNA editing events will be elucidated. Taken together, studies in this grant proposal will contribute to a better understanding of the roles of HDV RNA recombination and RNA editing in viral evolution.

Project ID:PC10512-0016
External Project ID:MOST105-2320-B182-042