scholarly journals Modeling Borna Disease Virus In Vitro Spread Reveals the Mode of Antiviral Effect Conferred by an Endogenous Bornavirus-Like Element

2020 ◽  
Vol 94 (21) ◽  
Author(s):  
Kwang Su Kim ◽  
Yusuke Yamamoto ◽  
Shinji Nakaoka ◽  
Keizo Tomonaga ◽  
Shingo Iwami ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Disease Virus ◽  
Virus Replication ◽  
Ground Squirrel ◽  
Cultured Cells ◽  
Antiviral Effect ◽  
Endogenous Retroviruses ◽  
Virus Spread ◽  
Borna Disease

ABSTRACT Endogenous retroviruses have demonstrated exaptation during long-term evolution with hosts, e.g., resulting in acquisition of antiviral effect on related extant viral infections. While empirical studies have found that an endogenous bornavirus-like element derived from viral nucleoprotein (itEBLN) in the ground squirrel genome shows antiviral effect on virus replication and de novo infection, the antiviral mechanism, dynamics, and quantitative effect of itEBLN remain unknown. In this study, we experimentally and theoretically investigated the dynamics of how an extant bornavirus, Borna disease virus 1 (BoDV-1), spreads and replicates in uninfected, BoDV-1-infected, and itEBLN-expressing cultured cells. Quantifying antiviral effect based on time course data sets, we found that the antiviral effects of itEBLN are estimated to be 75% and 34% on intercellular virus spread and intracellular virus replication, respectively. This discrepancy between intercellular virus spread and intracellular viral replication suggests that viral processes other than the replication of viral ribonucleoprotein complex (RNP) contributed to the suppression of virus spread in itEBLN-expressing cells. Because itEBLN binds to the BoDV-1 RNP, the suppression of viral RNP trafficking can be an attractive candidate explaining this discrepancy. IMPORTANCE Accumulating evidence suggests that some endogenous viral elements (EVEs), including endogenous retroviruses and endogenous nonretroviral virus elements, have acquired functions in the host as a result of long-term coevolution. Recently, an endogenous bornavirus-like element (itEBLN) found in the ground squirrel genome has been shown to have antiviral activity against exogenous bornavirus infection. In this study, we first quantified bornavirus spread in cultured cells and then calculated the antiviral activity of itEBLN on bornavirus infection. The calculated antiviral activity of itEBLN suggests its suppression of multiple processes in the viral life cycle. To our knowledge, this is the first study quantifying the antiviral activity of EVEs and speculating on a model of how some EVEs have acquired antiviral activity during host-virus arms races.

scholarly journals 2′-Fluoro-2′-Deoxycytidine Inhibits Borna Disease Virus Replication and Spread

2004 ◽  
Vol 48 (4) ◽  
pp. 1422-1425 ◽  
Author(s):  
Jeffrey J. Bajramovic ◽  
Romain Volmer ◽  
Sylvie Syan ◽  
Sylvie Pochet ◽  
Daniel Gonzalez-Dunia
Keyword(s):  
Side Effects ◽  
Antiviral Activity ◽  
Disease Virus ◽  
Virus Replication ◽  
Animal Species ◽  
Neurological Diseases ◽  
Borna Disease Virus ◽  
Warm Blooded Animal ◽  
Excellent Candidate ◽  
Borna Disease

ABSTRACT Borna disease virus (BDV) causes neurological diseases in a variety of warm-blooded animal species, possibly including humans. To date, there is no effective treatment against BDV infection. Recently, we reported on the antiviral activity of 1-β-d-arabinofuranosylcytosine (Ara-C). However, Ara-C's cytotoxic side effects are a major obstacle for its therapeutic use. Herein, we demonstrate that the nucleoside analog 2′-fluoro-2′-deoxycytidine (2′-FdC) exhibits potent antiviral activity against BDV. Importantly, 2′-FdC-associated cytotoxicity is negligible, indicating 2′-FdC as an excellent candidate for the development of antiviral therapy against BDV.

scholarly journals MEK-Specific Inhibitor U0126 Blocks Spread of Borna Disease Virus in Cultured Cells

2001 ◽  
Vol 75 (10) ◽  
pp. 4871-4877 ◽  
Author(s):  
Oliver Planz ◽  
Stephan Pleschka ◽  
Stephan Ludwig
Keyword(s):  
Disease Virus ◽  
Cultured Cells ◽  
Antiviral Drug ◽  
Specific Inhibitor ◽  
Host Cells ◽  
Virus Spread ◽  
Focus Formation ◽  
Borna Disease Virus ◽  
Borna Disease

ABSTRACT Borna disease virus (BDV) is a highly neurotropic virus that causes Borna disease, a virus-induced immune-mediated encephalomyelitis, in a variety of warm-blooded animals. Recent studies reported that BDV can be detected in patients with psychiatric disorders. BDV is noncytopathic, replicates in the nucleus of infected cells, and spreads intraaxonally in vivo. Upon infection of susceptible cultured cells, virus can be detected in foci. Little is known about the cellular components required for BDV replication. Here, we show that the cellular Raf/MEK/ERK signaling cascade is activated upon infection with BDV. In the presence of the MEK-specific inhibitor U0126, cells get infected with BDV; however, there is a block in virus spread to neighboring cells. The effect of the inhibitor on virus spread was still observed when the compound was added 2 h postinfection but not if treatment was initiated as late as 4 h after infection. Our results provide new insights into the BDV-host cell interaction and show that virus infection can be controlled with drugs interfering with a cellular signaling pathway. Since concentrations of the MEK inhibitor required to block BDV focus formation are not toxic for the host cells, our finding may be important with respect to antiviral drug development.

scholarly journals Inhibition of Borna Disease Virus Replication by Ribavirin

1999 ◽  
Vol 73 (9) ◽  
pp. 7903-7906 ◽  
Author(s):  
Ingo Jordan ◽  
Thomas Briese ◽  
Devron R. Averett ◽  
W. Ian Lipkin
Keyword(s):  
Antiviral Activity ◽  
Disease Virus ◽  
Cell Lines ◽  
Virus Replication ◽  
Antiviral Agent ◽  
Borna Disease Virus ◽  
Human Oligodendrocytes ◽  
Borna Disease ◽  
Neural Cell Lines

ABSTRACT The guanosine analogue ribavirin was tested for antiviral activity in two neural cell lines, human oligodendrocytes and rat glia, against Borna disease virus (BDV) strains V and He/80. Ribavirin treatment resulted in lower levels of virus and viral transcripts within 12 h. Addition of guanosine but not adenosine resulted in a profound reduction of the ribavirin effect. Ribavirin appears to be an effective antiviral agent for treatment of BDV infection in vitro. A likely mechanism for its activity is reduction of the intracellular GTP pool, resulting in inhibition of transcription and capping of BDV mRNAs.

Intracellular dynamics of actin affects Borna disease virus replication in the nucleus

2019 ◽  
Vol 263 ◽  
pp. 179-183 ◽  
Author(s):  
Yuya Hirai ◽  
Eisuke Domae ◽  
Yoshihiro Yoshikawa ◽  
Hideyuki Okamura ◽  
Akiko Makino ◽  
...  
Keyword(s):  
Disease Virus ◽  
Virus Replication ◽  
Borna Disease Virus ◽  
Borna Disease

scholarly journals EPSTI1 Is Involved in IL-28A-Mediated Inhibition of HCV Infection

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Xianghe Meng ◽  
Darong Yang ◽  
Rong Yu ◽  
Haizhen Zhu
Keyword(s):  
Life Cycle ◽  
Antiviral Activity ◽  
Viral Replication ◽  
Virus Replication ◽  
Antiviral Effect ◽  
Vital Role ◽  
Hcv Infection ◽  
Rnase L ◽  
Interferon Treatment

It has been reported that IFN-λs inhibit HCV replication in vitro. But the mechanisms of how IL-28A conducts antiviral activity and the functions of IL-28A-induced ISGs (IFN-stimulated genes) are not fully understood. In this study, we found that IL-28A has the antiviral effect on HCV life cycle including viral replication, assembly, and release. IL-28A and IFN-αsynergistically inhibit virus replication. EPSTI1 (epithelial-stromal interaction 1), one of IL-28A-induced ISGs, plays a vital role in IL-28A-mediated antiviral activity. Furthermore, forced expression of EPSTI1 effectively inhibits HCV replication in the absence of interferon treatment, and knockdown of EPSTI1 contributes to viral enhancement. EPSTI1 can activate PKR promoter and induce several PKR-dependent genes, including IFN-β, IFIT1, OAS1, and RNase L, which is responsible for EPSTI1-mediated antiviral activity.

scholarly journals Optimal Expression of the Envelope Glycoprotein of Orthobornaviruses Determines the Production of Mature Virus Particles

2020 ◽  
Author(s):  
Madoka Sakai ◽  
Yoko Fujita ◽  
Ryo Komorizono ◽  
Takehiro Kanda ◽  
Yumiko Komatsu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Disease Virus ◽  
Envelope Glycoprotein ◽  
Particle Production ◽  
Rna Virus ◽  
High Titer ◽  
Transduction Efficiency ◽  
Infectious Particle ◽  
Borna Disease

An RNA virus-based episomal vector (REVec) whose backbone is Borna disease virus 1 (BoDV-1) can provide long-term gene expression in transduced cells. To improve the transduction efficiency of REVec, we evaluated the role of the viral envelope glycoprotein (G) of the genus Orthobornavirus, including that of BoDV-1, in the production of infectious particles. By using G-pseudotype assay in which the lack of G in G-deficient REVec (ΔG-REVec) was compensated for expression of G, we found that excess expression of BoDV-1-G does not affect particle production itself but results in uncleaved and aberrant mature G expression in the cells, leading to the production of REVec particles with low transduction titers. We revealed that the expression of uncleaved G in the cells inhibits the incorporation of mature G and vgRNA into the particles. This feature of G was conserved among mammalian and avian orthobornaviruses; however, the cleavage efficacy of canary bornavirus 1 (CnBV-1)-G was exceptionally not impaired by its excess expression, which led to the production of the pseudotype ΔG-REVec with the highest titer. Chimeric G proteins between CnBV-1 and -2 revealed that the signal peptide of CnBV-1-G was responsible for the cleavage efficacy through the interaction with intracellular furin. We showed that CnBV-1 G leads to the development of pseudotyped REVec with high transduction efficiency and a high-titer recombinant REVec. Our study demonstrated that the restricted expression of orthobornavirus G contributes to the regulation of infectious particle production, the mechanism of which can improve the transduction efficiency of REVec. IMPORTANCE Most viruses causing persistent infection produce few infectious particles from the infected cells. Borna disease virus 1, a member of the genus Orthobornavirus, is an RNA virus that persistently infects the nucleus and has been applied to vectors for long-term gene expression. In this study, we showed that, common among orthobornaviruses, excessive G expression does not affect particle production itself but reduces the production of infectious particles with mature G and genomic RNA. This result suggested that limited G expression contributes to suppressing abnormal viral particle production. On the other hand, we found that canary bornavirus 1 has an exceptional G maturation mechanism and produces a high-titer virus. Our study will contribute to not only understanding the mechanism of infectious particle production but also improving the vector system of orthobornaviruses.

scholarly journals Alpha/Beta Interferon Promotes Transcription and Inhibits Replication of Borna Disease Virus in Persistently Infected Cells

2001 ◽  
Vol 75 (17) ◽  
pp. 8216-8223 ◽  
Author(s):  
Peter Staeheli ◽  
Maria Sentandreu ◽  
Axel Pagenstecher ◽  
Jürgen Hausmann
Keyword(s):  
Disease Virus ◽  
Cultured Cells ◽  
Genome Replication ◽  
Wild Type ◽  
Endogenous Virus ◽  
Viral Mrnas ◽  
Borna Disease Virus ◽  
Persistently Infected ◽  
Alpha Beta ◽  
Borna Disease

ABSTRACT Borna disease virus (BDV) is a noncytolytic RNA virus that can replicate in the central nervous system (CNS) of mice. This study shows that BDV multiplication was efficiently blocked in transgenic mice that express mouse alpha-1 interferon (IFN-α1) in astrocytes. To investigate whether endogenous virus-induced IFN might similarly restrict BDV, we usedIFNAR 0/0 mice, which lack a functional alpha/beta IFN (IFN-α/β) receptor. As would be expected if virus-induced IFN were important to control BDV infection, we found that cultured embryo cells of IFNAR 0/0 mice supported viral multiplication, whereas cells from wild-type mice did not. Unexpectedly, however, BDV spread through the CNSs ofIFNAR 0/0 and wild-type mice with similar kinetics, suggesting that activation of endogenous IFN-α/β genes in BDV-infected brains was too weak or occurred too late to be effective. Surprisingly, Northern blot analysis showed that the levels of the most abundant viral mRNAs in the brains of persistently infectedIFNAR 0/0 mice were about 20-fold lower than those in wild-type mice. In contrast, genomic viral RNA was produced in about a 10-fold excess in the brains ofIFNAR 0/0 mice. Human IFN-α2 similarly enhanced transcription and simultaneously repressed replication of the BDV genome in persistently infected Vero cells. Thus, in persistently infected neurons and cultured cells, IFN-α/β appears to freeze the BDV polymerase in the transcriptional mode, resulting in enhanced viral mRNA synthesis and suppressing viral genome replication.

Antiviral Activity of Some Hydroxycoumarin Derivatives

1996 ◽  
Vol 51 (7-8) ◽  
pp. 558-562 ◽  
Author(s):  
Angel S. Galabov ◽  
Tanya Iosifova ◽  
Elka Vassileva ◽  
Ivanka Kostova
Keyword(s):  
Antiviral Activity ◽  
Newcastle Disease Virus ◽  
Disease Virus ◽  
Virus Replication ◽  
Cell Cultures ◽  
Newcastle Disease ◽  
Inhibitory Effect ◽  
Marked Inhibitory Effect ◽  
Herpès Virus

Abstract Esculetin (6,7-dihydroxycoumarin) and its diacetate exhibited a marked inhibitory effect on Newcastle disease virus replication in cell cultures at concentrations of 36 jam and 62 jam, respectively. These compounds were selected from ten hydroxycoumarin derivatives through an in vitro antiviral screen involving viruses of the picorna-, orthomyxo-, paramyxo-, and herpes virus families.

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