A Novel Borna Disease Virus Vector System That Stably Expresses Foreign Proteins from an Intercistronic Noncoding Region

Daito, Takuji; Fujino, Kiyohisa; Honda, Takeshi; Matsumoto, Yusuke; Watanabe, Yohei; Tomonaga, Keizō

doi:10.1128/jvi.05554-11

Cited by 42 publications

(85 citation statements)

References 36 publications

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“…In addition, BDV is a candidate RNA virus vector for gene therapy of CNS cells because, unlike other potential virus vectors, BDV establishes a long-term persistent infection [98]. RNA viruses were thought to be better vectors for gene therapy than DNA viruses, because RNA viruses were believed to carry no risk of integration into their target cell rstb.royalsocietypublishing.org Phil Trans R Soc B 368: 20120499 genomic DNA.…”

Section: (B) Possible Novel Pathogenicity Of Borna Disease Virusmentioning

confidence: 99%

Comprehensive analysis of endogenous bornavirus-like elements in eukaryote genomes

Horie

Kobayashi

Suzuki

et al. 2013

Phil. Trans. R. Soc. B

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Bornaviruses are the only animal RNA viruses that establish a persistent infection in their host cell nucleus. Studies of bornaviruses have provided unique information about viral replication strategies and virus–host interactions. Although bornaviruses do not integrate into the host genome during their replication cycle, we and others have recently reported that there are DNA sequences derived from the mRNAs of ancient bornaviruses in the genomes of vertebrates, including humans, and these have been designated endogenous borna-like (EBL) elements. Therefore, bornaviruses have been interacting with their hosts as driving forces in the evolution of host genomes in a previously unexpected way. Studies of EBL elements have provided new models for virology, evolutionary biology and general cell biology. In this review, we summarize the data on EBL elements including what we have newly identified in eukaryotes genomes, and discuss the biological significance of EBL elements, with a focus on EBL nucleoprotein elements in mammalian genomes. Surprisingly, EBL elements were detected in the genomes of invertebrates, suggesting that the host range of bornaviruses may be much wider than previously thought. We also review our new data on non-retroviral integration of Borna disease virus.

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Section: (B) Possible Novel Pathogenicity Of Borna Disease Virusmentioning

confidence: 99%

Comprehensive analysis of endogenous bornavirus-like elements in eukaryote genomes

Horie

Kobayashi

Suzuki

et al. 2013

Phil. Trans. R. Soc. B

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“…Reverse-genetics approaches applied to BDV have demonstrated that the GFP gene can readily be inserted in the viral genome as an additional gene, thereby allowing the visualization of BDV dissemination in the CNS (22,23). Here, we aimed at inserting a fluorescent label in the context of a fusion construct with a structural protein.…”

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confidence: 99%

Analysis of Borna Disease Virus Trafficking in Live Infected Cells by Using a Virus Encoding a Tetracysteine-Tagged P Protein

Charlier

Allart

et al. 2013

J Virol

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f Borna disease virus (BDV) is a nonsegmented, negative-stranded RNA virus characterized by noncytolytic persistent infection and replication in the nuclei of infected cells. To gain further insight on the intracellular trafficking of BDV components during infection, we sought to generate recombinant BDV (rBDV) encoding fluorescent fusion viral proteins. We successfully rescued a virus bearing a tetracysteine tag fused to BDV-P protein, which allowed assessment of the intracellular distribution and dynamics of BDV using real-time live imaging. In persistently infected cells, viral nuclear inclusions, representing viral factories tethered to chromatin, appeared to be extremely static and stable, contrasting with a very rapid and active trafficking of BDV components in the cytoplasm. Photobleaching (fluorescence recovery after photobleaching [FRAP] and fluorescence loss in photobleaching [FLIP]) imaging approaches revealed that BDV components were permanently and actively exchanged between cellular compartments, including within viral inclusions, albeit with a fraction of BDV-P protein not mobile in these structures, presumably due to its association with viral and/or cellular proteins. We also obtained evidence for transfer of viral material between persistently infected cells, with routing of the transferred components toward the cell nucleus. Finally, coculture experiments with noninfected cells allowed visualization of cell-to-cell BDV transmission and movement of the incoming viral material toward the nucleus. Our data demonstrate the potential of tetracysteine-tagged recombinant BDV for virus tracking during infection, which may provide novel information on the BDV life cycle and on the modalities of its interaction with the nuclear environment during viral persistence. Borna disease virus (BDV) is an enveloped virus with a nonsegmented, negative-strand RNA genome (1, 2), which represents the prototypic member of the family Bornaviridae. In contrast to other Mononegavirales members, BDV replicates in the nuclei of infected cells (3) and uses the host cell splicing machinery for maturation of viral transcripts (4, 5). The BDV compact genome encodes six proteins, namely, the nucleoprotein (N), phosphoprotein (P), protein X, matrix protein (M), glycoprotein (G), and polymerase (L). Whereas M and G are involved in particle formation, P, N, and L are components of the ribonucleoprotein complex (RNP). The small X protein has been shown to contribute to apoptosis resistance during infection (6) and may also have interferon antagonist activities (7). BDV persistently infects a wide range of mammalian and avian species (8-11), resulting in a large spectrum of neurological disorders ranging from immune-mediated diseases to behavioral syndromes without inflammation (8, 12, 13). BDV is highly neurotropic but can also replicate in other cells of the central nervous system (CNS), as well as in many established cell lines in vitro (9).To date, the BDV cell cycle remains poorly characterized. It is known that BDV enters ce...

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“…Confirmation of exclusive tumor targeting following localized or systemic delivery of oncolytic virotherapies has been demonstrated with a luciferase-expressing recombinant Newcastle disease virus (Wei et al, 2012) and a measles virus expressing the human thyroidal sodium ion symporter (which concentrates radioisotopes inside cells) allowing for PET or SPECT/CT imaging in mice (Msaouel et al, 2009). GFP has been used to demonstrate that a modified Borna disease virus vector may have utility for stable gene expression in the central nervous system (Daito et al, 2011), and GFP-expressing Rabies viruses have been instrumental in studies on neuroarchitecture (Wickersham et al, 2007a; Wickersham et al, 2007b). Based on experiences with other viruses, reporter-expressing mononegaviruses also have the potential for additional uses in vivo such as monitoring the effectiveness of anti-viral therapies and vaccine studies in real time or more detailed pathogenesis studies (both real time and post-mortem) - including determining the effects of viral factors, host genetics, host age, immune status, environmental and inoculation conditions on infection dynamics and transmission (Burke et al, 2011).…”

Section: Applications Of Reporter-expressing Virusesmentioning

confidence: 99%

“…Therefore, GFP is not optimal for in vivo imaging, unless virus replication occurs at or near the surface of infected animals, such as the skin or mucosae (Ludlow et al, 2012). Despite this, GFP has been very successfully used for ex vivo imaging (Daito et al, 2011; de Swart et al, 2007; von Messling et al, 2004). Recently, red and far red fluorescent reporters are being increasingly used, including mCherry (Hoenen et al, 2012; Shi et al, 2010), (t)dTomato (Ludlow et al, 2012; Wiener et al, 2010), dsRed (Daito et al, 2011; Takeda et al, 2006), red fluorescent protein (RFP) (Dinh et al, 2012; Kim et al, 2013) and Katushka2 (Hotard et al, 2012).…”

Section: Challenges In the Development And Application Of Reportermentioning

confidence: 99%

“…Despite this, GFP has been very successfully used for ex vivo imaging (Daito et al, 2011; de Swart et al, 2007; von Messling et al, 2004). Recently, red and far red fluorescent reporters are being increasingly used, including mCherry (Hoenen et al, 2012; Shi et al, 2010), (t)dTomato (Ludlow et al, 2012; Wiener et al, 2010), dsRed (Daito et al, 2011; Takeda et al, 2006), red fluorescent protein (RFP) (Dinh et al, 2012; Kim et al, 2013) and Katushka2 (Hotard et al, 2012). The availability of these proteins might significantly improve our ability to perform in vivo imaging studies, as their excitation and emission wavelengths allow greater tissue penetration, and some of them are also brighter than GFP (Table 1) (Deliolanis et al, 2008); however, this remains to be demonstrated.…”

Section: Challenges In the Development And Application Of Reportermentioning

confidence: 99%

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Development and application of reporter-expressing mononegaviruses: Current challenges and perspectives

2014

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Reverse genetics allows the generation of recombinant viruses entirely from cDNA. One application of this technology is the creation of reporter-expressing viruses, which greatly increase the detail and ease with which these viruses can be studied. However, there are a number of challenges when working with reporter-expressing viruses. Both the reporter protein itself as well as the genetic manipulations within the viral genome required for expression of this reporter can result in altered biological properties of the recombinant virus, and lead to attenuation in vitro and/or in vivo. Further, instability of reporter expression and purging of the genetic information encoding for the reporter from the viral genome can be an issue. Finally, a practical challenge for in vivo studies lies in the attenuation of light signals when traversing tissues. Novel expression strategies and the continued development of brighter, red and farred shifted reporters and the increased use of bioluminescent reporters for in vivo applications promise to overcome some of these limitations in future. However, a “one size fits all” approach to the design of reporter-expressing viruses has thus far not been possible. Rather, a reporter suited to the intended application must be selected and an appropriate expression strategy and location for the reporter in the viral genome chosen. Still, attenuating effects of the reporter on viral fitness are difficult to predict and have to be carefully assessed with respect to the intended application. Despite these limitations the generation of suitable reporter-expressing viruses will become more common as technology and our understanding of the intricacies of viral gene expression and regulation improves, allowing deeper insight into virus biology both in living cells and in animals.

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A Novel Borna Disease Virus Vector System That Stably Expresses Foreign Proteins from an Intercistronic Noncoding Region

Cited by 42 publications

References 36 publications

Comprehensive analysis of endogenous bornavirus-like elements in eukaryote genomes

Comprehensive analysis of endogenous bornavirus-like elements in eukaryote genomes

Analysis of Borna Disease Virus Trafficking in Live Infected Cells by Using a Virus Encoding a Tetracysteine-Tagged P Protein

Development and application of reporter-expressing mononegaviruses: Current challenges and perspectives

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