Research Papers: Immunology:

Analyses of a whole-genome inter-clade recombination map of hepatitis delta virus suggest a host polymerase-driven and viral RNA structure-promoted template-switching mechanism for viral RNA recombination

Mei Chao _, Tzu-Chi Wang, Chia-Chi Lin, Robert Yung-Liang Wang, Wen-Bin Lin, Shang-En Lee, Ying-Yu Cheng, Chau-Ting Yeh and Shan-Bei Iang

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Oncotarget. 2017; 8:60841-60859. https://doi.org/10.18632/oncotarget.18339

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Mei Chao1,2,3, Tzu-Chi Wang2,*, Chia-Chi Lin2, Robert Yung-Liang Wang2,4, Wen-Bin Lin2, Shang-En Lee2, Ying-Yu Cheng2, Chau-Ting Yeh3 and Shan-Bei Iang2

1 Department of Microbiology and Immunology, Chang Gung University, Guishan, Taoyang, Taiwan

2 Division of Microbiology, Graduate Institute of Biomedical Sciences, Chang Gung University, Guishan, Taoyang, Taiwan

3 Department of Hepato-Gastroenterology, Liver Research Center, Chang Gung Memorial Hospital, Guishan, Taoyang, Taiwan

4 Department of Biomedical Sciences, Chang Gung University, Guishan, Taoyang, Taiwan

* Deceased

Correspondence to:

Mei Chao, email:

Keywords: hepatitis delta virus, mammalian RNA polymerase, ribozyme, RNA recombination, template-switching, Immunology and Microbiology Section, Immune response, Immunity

Received: November 09, 2016 Accepted: May 22, 2017 Published: June 01, 2017


The genome of hepatitis delta virus (HDV) is a 1.7-kb single-stranded circular RNA that folds into an unbranched rod-like structure and has ribozyme activity. HDV redirects host RNA polymerase(s) (RNAP) to perform viral RNA-directed RNA transcription. RNA recombination is known to contribute to the genetic heterogeneity of HDV, but its molecular mechanism is poorly understood. Here, we established a whole-genome HDV-1/HDV-4 recombination map using two cloned sequences coexisting in cultured cells. Our functional analyses of the resulting chimeric delta antigens (the only viral-encoded protein) and recombinant genomes provide insights into how recombination promotes the genotypic and phenotypic diversity of HDV. Our examination of crossover distribution and subsequent mutagenesis analyses demonstrated that ribozyme activity on HDV genome, which is required for viral replication, also contributes to the generation of an inter-clade junction. These data provide circumstantial evidence supporting our contention that HDV RNA recombination occurs via a replication-dependent mechanism. Furthermore, we identify an intrinsic asymmetric bulge on the HDV genome, which appears to promote recombination events in the vicinity. We therefore propose a mammalian RNAP-driven and viral-RNA-structure-promoted template-switching mechanism for HDV genetic recombination. The present findings improve our understanding of the capacities of the host RNAP beyond typical DNA-directed transcription.

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