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

ABSTRACT

Human herpesvirus 6B (HHV-6B), a member of the Betaherpesvirinae subfamily, is a T-lymphotropic virus that causes exanthem subitum and has been implicated in neuroinflammatory conditions such as multiple sclerosis. The tegument proteins, which are characteristic of herpesviruses, play a crucial role in the envelopment of virions and evasion of host immune defenses, such as the interferon β (IFNβ) signaling pathway. However, the precise mechanisms through which the HHV-6B tegument proteins modulate the IFNβ pathway are not yet fully understood. In this study, we identified a novel function of the HHV-6B tegument protein U65 as an inhibitor of IFNβ production. Additionally, two host histone proteins, hCG_2039566 (H2ACG) and H2AC7, were identified as positive regulators of innate immune pathways. U65 interacts with H2ACG and H2AC7, impairing their ability to promote the IFNβ pathway. Furthermore, we demonstrated that U65 plays critical roles during HHV-6B infection. This study highlights a critical strategy employed by HHV-6B to evade immune defenses, shedding light on its mechanisms for counteracting host responses.

IMPORTANCE

HHV-6B is a virus that primarily infects T cells and can cause illnesses like exanthem subitum and is linked to neurological conditions such as multiple sclerosis. Like other herpesviruses, HHV-6B likely has special proteins that help it avoid the body’s immune defenses, such as the IFNβ signaling pathway, which plays a key role in fighting viral infections. However, how these viral proteins interfere with the immune response is not yet fully understood. In this study, we discovered that one of the HHV-6B proteins, U65, blocks the production of IFNβ, weakening the antiviral defenses. We also found that two human proteins, hCG_2039566 and H2AC7, promote the immune system, but U65 prevents them from doing so. This study reveals a new way that HHV-6B escapes the immune system, providing insight into how the virus efficiently establishes infections and how we might target its ability to evade immunity.

DOI： 10.1128/jvi.00984-25

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Borna disease virus (BoDV-1) is a bornavirus prototype that infects the central nervous system of various animal species and can cause fatal encephalitis in various animals including humans. Among the reported anti-BoDV-1 treatments, favipiravir (T-705) is one of the best candidates since it has been shown to be effective in reducing various bornavirus titers in cell culture. However, T-705 effectiveness on BoDV-1 is cell type-dependent, and the molecular mechanisms that explain this cell type-dependent difference remain unknown. In this study, we noticed a fact that T-705 efficiently suppressed BoDV-1 in infected 293T cells, but not in infected SH-SY5Y cells, and sought to identify protein(s) responsible for this cell-type-dependent difference in T-705 efficacy. By comparing the transcriptomes of BoDV-1-infected 293T and SH-SY5Y cells, we identified heart- and neural crest derivatives-expressed protein 2 (HAND2) as a candidate involved in T-705 interference. HAND2 overexpression partly attenuated the inhibitory effect of T-705, whereas HAND2 knockdown enhanced this effect. We also demonstrated an interaction between T-705 and HAND2. Furthermore, T-705 impaired HAND2-mediated host gene expression. Because HAND2 is an essential transcriptional regulator of embryogenesis, T-705 may exhibit its adverse effects such as teratogenicity and embryotoxicity through the impairment of HAND2 function. This study provides novel insights into the molecular mechanisms underlying T-705 interference in some cell types and inspires the development of improved T-705 derivatives for the treatment of RNA viruses.

DOI： 10.1016/j.antiviral.2024.105812

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Borna disease virus (BoDV-1) is a highly neurotropic RNA virus that causes neurobehavioral disturbances such as abnormal social activities and memory impairment. Although impairments in the neural circuits caused by BoDV-1 infection induce these disturbances, the molecular basis remains unclear. Furthermore, it is unknown whether anti-BoDV-1 treatments can attenuate BoDV-1-mediated transcriptomic changes in neuronal cells. In this study, we investigated the effects of BoDV-1 infection on neuronal differentiation and the transcriptome of differentiated neuronal cells using persistently BoDV-1-infected cells. Although BoDV-1 infection did not have a detectable effect on intracellular neuronal differentiation processes, differentiated neuronal cells exhibited transcriptomic changes in differentiation-related genes. Some of these transcriptomic changes, such as the decrease in the expression of apoptosis-related genes, were recovered by anti-BoDV-1 treatment, while alterations in the expression of other genes remained after treatment. We further demonstrated that a decrease in cell viability induced by differentiation processes in BoDV-1-infected cells can be relieved with anti-BoDV-1 treatment. This study provides fundamental information regarding transcriptomic changes after BoDV-1 infection and the treatment in neuronal cells.

DOI： 10.3390/v15040942

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Long interspersed element 1 (LINE-1, or L1) is a retrotransposon that constitutes ~ 17% of the human genome. Although ~ 6000 full-length L1s spread throughout the human genome, their biological significance remains undetermined. The L1 5' untranslated region has bidirectional promoter activity with a sense promoter driving L1 mRNA production and an antisense promoter (ASP) driving the production of L1-gene chimeric RNAs. Here, we stimulated L1 ASP activity using CRISPR-Cas9 technology to evaluate its biological impacts. Activation of the L1 ASP upregulated the expression of L1 ASP-driven ORF0 and enhanced cell growth. Furthermore, the exogenous expression of ORF0 also enhanced cell growth. These results indicate that activation of L1 ASP activity fuels cell growth at least through ORF0 expression. To our knowledge, this is the first report demonstrating the role of the L1 ASP in a biological context. Considering that L1 sequences are desilenced in various tumor cells, our results indicate that activation of the L1 ASP may be a cause of tumor growth; therefore, interfering with L1 ASP activity may be a potential strategy to suppress the growth.

DOI： 10.1038/s41598-020-79197-y

PubMed

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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

PubMed

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開催年月日： 2025年10月28日 - 2025年10月30日

記述言語：英語   会議種別：口頭発表（一般）  

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開催年月日： 2025年10月11日 - 2025年10月12日

記述言語：中国語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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開催年月日： 2024年11月4日 - 2024年11月6日

記述言語：英語   会議種別：口頭発表（一般）  

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開催年月日： 2023年9月26日 - 2023年9月28日

記述言語：英語   会議種別：口頭発表（一般）  

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開催年月日： 2023年9月17日 - 2023年9月19日

記述言語：英語   会議種別：ポスター発表  

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