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Modeling Borna Disease Virus In Vitro Spread Reveals the Mode of Antiviral Effect Conferred by an Endogenous Bornavirus-Like Element 査読国際誌

Kwang Su Kim, Yusuke Yamamoto, Shinji Nakaoka, Keizo Tomonaga, Shingo Iwami, Tomoyuki Honda

Journal of Virology 94 ( 21 ) e01204-20 2020年8月

Complete Genome Sequence of a Precore-Defective Hepatitis B Virus Genotype D2 Strain Isolated in Bangladesh. 査読国際誌

Md Golzar Hossain, Md Muket Mahmud, Md Arifur Rahman, Sharmin Akter, K H M Nazmul Hussain Nazir, Sukumar Saha, Masami Wada, Eriko Ohsaki, Tomoyuki Honda, Keiji Ueda

Microbiology resource announcements 9 ( 11 ) 2020年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Hepatitis B virus (HBV) genomic mutations affect viral replication, disease progression, and diagnostic and vaccination efficiency. There is limited information regarding characterization and mutational analysis of HBV isolated in Bangladesh. Here, we report the complete nucleotide sequence of a precore-defective HBV genotype D2 strain isolated in Bangladesh.

DOI： 10.1128/MRA.00083-20

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Kaposi’s sarcoma-associated herpesvirus is cell-intrinsically controlled in latency in microgravity. 査読国際誌

Honda T, Nakayama R, Kawahara Y, Yuge L, Ueda K

Virus Research 276 197821 - 197821 2020年1月

Relaunching human bornavirus research from severe encephalitis cases with unclear etiology 招待査読

Honda T

The Lancet Infectious Diseases in press 2020年1月

RNA Virus-Based Episomal Vector with a Fail-Safe Switch Facilitating Efficient Genetic Modification and Differentiation of iPSCs. 査読国際誌

Yumiko Komatsu, Dan Takeuchi, Tomoya Tokunaga, Hidetoshi Sakurai, Akiko Makino, Tomoyuki Honda, Yasuhiro Ikeda, Keizo Tomonaga

Molecular therapy. Methods & clinical development 14 47 - 55 2019年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

A gene delivery system that allows efficient and safe stem cell modification is critical for next-generation stem cell therapies. An RNA virus-based episomal vector (REVec) is a gene transfer system developed based on Borna disease virus (BoDV), which facilitates persistent intranuclear RNA transgene delivery without integrating into the host genome. In this study, we analyzed susceptibility of human induced pluripotent stem cell (iPSC) lines from different somatic cell sources to REVec, along with commonly used viral vectors, and demonstrated highly efficient REVec transduction of iPSCs. Using REVec encoding myogenic transcription factor MyoD1, we further demonstrated potential application of the REVec system for inducing differentiation of iPSCs into skeletal muscle cells. Of note, treatment with a small molecule, T-705, completely eliminated REVec in persistently transduced cells. Thus, the REVec system offers a versatile toolbox for stable, integration-free iPSC modification and trans-differentiation, with a unique switch-off mechanism.

DOI： 10.1016/j.omtm.2019.05.010

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Identification of a Retroelement-Containing Human Transcript Induced in the Nucleus by Vaccination. 査読国際誌

Tomoyuki Honda, Keiko Takemoto, Keiji Ueda

International journal of molecular sciences 20 ( 12 ) 2875 2019年6月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Endogenous retroelements constitute almost half of the mammalian genome. Given that more than 60% of human genomic bases are transcribed, transcripts containing these retroelements may impact various biological processes. However, the physiological roles of most retroelement-containing transcripts are yet to be revealed. Here, we profiled the expression of retroelement-containing human transcripts during vaccination and found that vaccination upregulated transcripts containing only particular retroelements, such as the MLT-int element of endogenous retroviruses. MLT-int-containing transcripts were distributed mainly in the nucleus, suggesting their unique roles in the nucleus. Furthermore, we demonstrated that MLT-int RNA suppressed interferon promoter activity in the absence of immune stimuli. Based on these lines of evidence, we speculate a model of a role of the previously unnoticed MLT-int element in preventing excess innate immune activation after elimination of immune stimuli. Our results may emphasize the importance of retroelement-containing transcripts in maintaining host immune homeostasis.

DOI： 10.3390/ijms20122875

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Latent infection with Kaposi’s sarcoma-associated herpesvirus enhances retrotransposition of long interspersed element-1. 査読国際誌

Nakayama R, Ueno Y, Ueda K, Honda T

Oncogene 38 ( 22 ) 4340 - 4351 2019年5月

Profiling of LINE-1-Related Genes in Hepatocellular Carcinoma. 招待査読

Honda T, Rahman MA

International Journal of Molecular Sciences 20 ( 3 ) 645 2019年2月

A Small Interfering RNA Cocktail Targeting the Nucleoprotein and Large Protein Genes Suppresses Borna Disease Virus Infection. 査読国際誌

Da Teng, Shunsuke Obika, Keiji Ueda, Tomoyuki Honda

Frontiers in microbiology 10 2781 - 2781 2019年

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Recently, Borna disease virus (BoDV-1)-related fatal encephalitis human cases have been reported, which highlights the potential of BoDV-1 to cause fatal human diseases. To protect the infected brain from lethal damage, it is critical to control BoDV-1 as quickly as possible. At present, antivirals against BoDV-1 are limited, and therefore, novel types of antivirals are needed. Here, we developed a novel treatment using small interfering RNAs (siRNAs) against BoDV-1. We screened several siRNAs targeting the viral N, M, and L genes for BoDV-1-reducing activity. Among the screened candidates, we chose two siRNAs that efficiently decreased the BoDV-1 load in persistently BoDV-1-infected cells to prepare a siRNA cocktail (TD-Borna) for BoDV-1 treatment. TD-Borna successfully reduced the BoDV-1 load without enhancing the risk of emergence of escape mutants. The combination of TD-Borna and T-705, a previously reported antiviral agent against bornaviruses, decreased the BoDV-1 load more efficiently than TD-Borna or T-705 alone. Furthermore, TD-Borna efficiently decreased the BoDV-1 load in BoDV-1-infected neuron-derived cells, in which T-705 did not decrease the viral load. Overall, we developed a novel antiviral candidate against BoDV-1, TD-Borna, that can be used in combination with T-705 and is effective against BoDV-1 in neuron-derived cells, in which T-705 is less effective. Considering that BoDV-1 is highly neurotropic, TD-Borna can offer a promising option to improve the outcome of BoDV-1 infection.

DOI： 10.3389/fmicb.2019.02781

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Development of an RNA Virus-Based Episomal Vector Capable of Switching Transgene Expression. 査読国際誌

Yusuke Yamamoto, Keizo Tomonaga, Tomoyuki Honda

Frontiers in microbiology 10 2485 - 2485 2019年

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Viral vectors are efficient gene delivery systems, although most of these vectors still present limitations to their practical use, such as achieving only transient transgene expression and a risk of insertional mutations. We have recently developed an RNA virus-based episomal vector (REVec), based on nuclear-replicating Borna disease virus (BoDV). REVec can transduce transgenes into various types of cells and stably express transgenes; however, an obstacle to the practical use of REVec is the lack of a mechanism to turn off transgene expression once REVec is transduced. Here, we developed a novel REVec system, REVec-L2b9, in which transgene expression can be switched on and off by using a theophylline-dependent self-cleaving riboswitch. Transgene expression from REVec-L2b9 was suppressed in the absence of theophylline and induced by theophylline administration. Conversely, transgene expression from REVec-L2b9 was switched off by removing theophylline. To our knowledge, REVec-L2b9 is the first nuclear-replicating RNA virus vector capable of switching transgene expression on and off as needed, which will expand the potential for gene therapies by increasing safety and usability.

DOI： 10.3389/fmicb.2019.02485

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Inhibition of LINE-1 Retrotransposition by Capsaicin. 査読国際誌

Yuki Nishikawa, Ryota Nakayama, Shunsuke Obika, Eriko Ohsaki, Keiji Ueda, Tomoyuki Honda

International journal of molecular sciences 19 ( 10 ) 2018年10月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Long interspersed nuclear element 1 (LINE-1 or L1) is a non-long terminal repeat (LTR) retrotransposon that constitutes approximately 17% of the human genome. Since approximately 100 copies are still competent for retrotransposition to other genomic loci, dysregulated retrotransposition of L1 is considered to be a major risk factor of endogenous mutagenesis in humans. Thus, it is important to find drugs to regulate this process. Although various chemicals are reportedly capable of affecting L1 retrotransposition, it is poorly understood whether phytochemicals modulate L1 retrotransposition. Here, we screened a library of compounds that were derived from phytochemicals for reverse transcriptase (RT) inhibition with an in vitro RT assay. We identified capsaicin as a novel RT inhibitor that also suppressed L1 retrotransposition. The inhibitory effect of capsaicin on L1 retrotransposition was mediated neither through its receptor, nor through its modulation of the L1 promoter and/or antisense promoter activity, excluding the possibility that capsaicin indirectly affected L1 retrotransposition. Collectively, capsaicin suppressed L1 retrotransposition most likely by inhibiting the RT activity of L1 ORF2p, which is the L1-encoded RT responsible for L1 retrotransposition. Given that L1-mediated mutagenesis can cause tumorigenesis, our findings suggest the potential of capsaicin for suppressing cancer development.

DOI： 10.3390/ijms19103243

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Two Neuropsychiatric Cases Seropositive for Bornavirus Improved by Ribavirin 査読

Hidenori Matsunaga, Akio Fukumori, Kohji Mori, Tomoyuki Honda, Takeshi Uema, Keizo Tomonaga

Japanese Journal of Infectious Diseases 71 ( 5 ) 338 - 342 2018年9月

vFLIP upregulates IKKε, leading to spindle morphology formation through RelA activation. 査読国際誌

Yang Z, Honda T, Ueda K

Virology 522 106 - 121 2018年9月

Prevalence of antibodies against Borna disease virus proteins in Japanese children with autism spectrum disorder. 査読国際誌

Tomoyuki Honda, Kozue Sofuku, Hidenori Matsunaga, Masaya Tachibana, Ikuko Mohri, Masako Taniike, Keizo Tomonaga

Microbiology and immunology 2018年5月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Bornavirus infection is observed in both animals, including humans. However, bornavirus epidemiology in humans, especially in children, remains unclear. Here, we evaluated antibodies against bornaviruses in Japanese children with autism spectrum disorder (ASD) using immunofluorescence analysis, western blotting, and radio ligand assay. The prevalence of antibodies against bornavirus-specific speckles, N, and P proteins were 22%, 48%, and 33%, respectively, in the ASD children. According to our criteria, the prevalence of antibodies against bornaviruses was 7.4% in the ASD children. This is the first report of the serological prevalence of bornavirus in Japanese children. Our results provide valuable baseline-data regarding bornavirus epidemiology in children for future studies.

DOI： 10.1111/1348-0421.12603

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A single amino acid substitution within the paramyxovirus Sendai virus nucleoprotein is a critical determinant for production of interferon-beta-inducing copyback-type defective interfering genomes 査読

Asuka Yoshida, Ryoko Kawabata, Tomoyuki Honda, Kouji Sakai, Yasushi Ami, Takemasa Sakaguchi, Takashi Irie

Journal of Virology 92 ( 5 ) 2018年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：American Society for Microbiology

One of the first defenses against infecting pathogens is the innate immune system activated by cellular recognition of pathogen-associated molecular patterns (PAMPs). Although virus-derived RNA species, especially copyback (cb)-type defective interfering (DI) genomes, have been shown to serve as real PAMPs, which strongly induce interferon-beta (IFN-β) during mononegavirus infection, the mechanisms underlying DI generation remain unclear. Here, for the first time, we identified a single amino acid substitution causing production of cbDI genomes by successful isolation of two distinct types of viral clones with cbDI-producing and cbDI-nonproducing phenotypes from the stock Sendai virus (SeV) strain Cantell, which has been widely used in a number of studies on antiviral innate immunity as a representative IFN-β-inducing virus. IFN-β induction was totally dependent on the presence of a significant amount of cbDI genomecontaining viral particles (DI particles) in the viral stock, but not on deficiency of the IFNantagonistic viral accessory proteins C and V. Comparison of the isolates indicated that a single amino acid substitution found within the N protein of the cbDI-producing clone was enough to cause the emergence of DI genomes. The mutated N protein of the cbDI-producing clone resulted in a lower density of nucleocapsids than that of the DInonproducing clone, probably causing both production of the DI genomes and their formation of a stem-loop structure, which serves as an ideal ligand for RIG-I. These results suggested that the integrity of mononegaviral nucleocapsids might be a critical factor in avoiding the undesirable recognition of infection by host cells.

DOI： 10.1128/JVI.02094-17

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Influence of Endogenous Viral Sequences on Gene Expression. 査読

Sofuku K, Honda T

Gene Expression and Regulation in Mammalian Cells 67 - 80 2018年

Importance of Promyelocytic Leukema Protein (PML) for Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication. 査読国際誌

Md Golzar Hossain, Eriko Ohsaki, Tomoyuki Honda, Keiji Ueda

Frontiers in microbiology 9 2324 - 2324 2018年

記述言語：英語掲載種別：研究論文（学術雑誌）

Many DNA virus replication-related proteins are associated with promyelocytic leukemia protein (PML), a component of nuclear domain 10 (ND10), which has been investigated for its potential involvement in viral replication. In the case of Kaposi's sarcoma-associated herpesvirus (KSHV) lytic gene products, K8 (K-bZIP), ORF59, and ORF75 have been shown to colocalize with PML, but its importance in KSHV lytic replication is still unclear. In this study, we analyzed the functional influence of PML on KSHV latency and lytic replication in KSHV-infected primary effusion lymphoma (PEL) cell lines. Stable PML-knockout (BC3-PMLKO) and PML-overexpressing BC3 cells (BC3PML) were successfully generated and the latency and reactivation status were analyzed. The results demonstrated that neither KSHV latency nor the episome copy number was affected in BC3-PMLKO cells. In the reactivation phase, the expression dynamics of KSHV immediate-early or early lytic proteins such as RTA, K9 (vIRF1), K5, K3, ORF59, and K8 (K-bZIP) were comparable between wild-type, control BC3, and BC3-PMLKO cells. Interestingly, KSHV lytic replication, virion production, and expression of late genes were downregulated in BC3-PMLKO cells and upregulated in BC3PML cells, compared to those in control or wild-type BC3 cells. Moreover, exogenous PML increased the size of the PML dots and recruited additional K8 (K-bZIP) to PML-NBs as dots. Therefore, PML would function as a positive regulator for KSHV lytic DNA replication by recruiting KSHV replication factors such as 8 (K-bZIP) or ORF59 to the PML-NBs.

DOI： 10.3389/fmicb.2018.02324

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Potential Links between Hepadnavirus and Bornavirus Sequences in the Host Genome and Cancer 査読

Tomoyuki Honda

FRONTIERS IN MICROBIOLOGY 8 2537 2017年12月

担当区分：筆頭著者,　責任著者記述言語：英語出版者・発行元：FRONTIERS MEDIA SA

Various viruses leave their sequences in the host genomes during infection. Such events occur mainly in retrovirus infection but also sometimes in DNA and non-retroviral RNA virus infections. If viral sequences are integrated into the genomes of germ line cells, the sequences can become inherited as endogenous viral elements (EVEs). The integration events of viral sequences may have oncogenic potential. Because proviral integrations of some retroviruses and/or reactivation of endogenous retroviruses are closely linked to cancers, viral insertions related to non-retroviral viruses also possibly contribute to cancer development. This article focuses on genomic viral sequences derived from two non-retroviral viruses, whose endogenization is already reported, and discusses their possible contributions to cancer. Viral insertions of hepatitis B virus play roles in the development of hepatocellular carcinoma. Endogenous bornavirus-like elements, the only non-retroviral RNA virus-related EVEs found in the human genome, may also be involved in cancer formation. In addition, the possible contribution of the interactions between viruses and retrotransposons, which seem to be a major driving force for generating EVEs related to non-retroviral RNA viruses, to cancers will be discussed. Future studies regarding the possible links described here may open a new avenue for the development of novel therapeutics for tumor virus-related cancers and/or provide novel insights into EVE functions.

DOI： 10.3389/fmicb.2017.02537

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Linkage between the leader sequence and leader RNA production in Borna disease virus-infected cells 査読

Tomoyuki Honda, Kozue Sofuku, Shohei Kojima, Yusuke Yamamoto, Naohiro Ohtaki, Keizo Tomonaga

VIROLOGY 510 104 - 110 2017年10月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE

The 3'-untranslated region (UTR) of the non-segmented, negative-strand (NNS) RNA viral genome is called the leader sequence, and functions as the promoter for viral replication and transcription. NNS RNA viruses also use the sequence as a template to synthesize leader RNAs (leRNAs) with unknown functions. Borna disease virus (BDV) is unique because it establishes a persistent infection and replicates in the nucleus. No report has yet demonstrated the presence of leRNAs during BDV infection. Here, we report that BDV synthesizes leRNAs from the 3'-UTR of the genome. They started at position 5 in the 3'-UTR and ended by the transcription start signal of the nucleoprotein gene. The level of leRNA production is not correlated with the levels of viral replication and transcription. On the other hand, mutation of the 3'-UTR affects leRNA production. Our findings add a novel viral transcript to the BDV life cycle and shed light on BDV replication and/or transcription.

DOI： 10.1016/j.virol.2017.07.011

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Detection of Antibodies against Borna Disease Virus Proteins in an Autistic Child and Her Mother (vol 70, pg 225, 2017) 査読

Tomoyuki Honda, Kozue Sofuku, Hidenori Matsunaga, Masaya Tachibana, Ikuko Mohri, Masako Taniike, Keizo Tomonaga

JAPANESE JOURNAL OF INFECTIOUS DISEASES 70 ( 5 ) 599 - 599 2017年9月

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