The challenges in combating enteroviruses continue due to their genetic diversity and the rapid development of resistance. Combining antiviral agents offers a promising solution. Our study evaluated the combined effects of pocapavir, a potent capsid-binding inhibitor, with enterovirus-targeting compounds such as pleconaril, 2-(3,4-dichlorophenoxy)-5-nitrobenzonitrile (MDL-860), guanidine hydrochloride, oxoglaucine, and 2-α-hydroxybenzyl-benzimidazole (HBB). The combinations tested demonstrated additive to highly synergistic antiviral effects without observed combined cytotoxicity. These results suggest their potential for further research and clinical trials in combating enterovirus infections.
{"title":"Antiviral activity in vitro of double combinations of enteroviral inhibitors","authors":"A. Stoyanova, S. Galabov, A.S. Galabov","doi":"10.3389/av.2024.12361","DOIUrl":"https://doi.org/10.3389/av.2024.12361","url":null,"abstract":"The challenges in combating enteroviruses continue due to their genetic diversity and the rapid development of resistance. Combining antiviral agents offers a promising solution. Our study evaluated the combined effects of pocapavir, a potent capsid-binding inhibitor, with enterovirus-targeting compounds such as pleconaril, 2-(3,4-dichlorophenoxy)-5-nitrobenzonitrile (MDL-860), guanidine hydrochloride, oxoglaucine, and 2-α-hydroxybenzyl-benzimidazole (HBB). The combinations tested demonstrated additive to highly synergistic antiviral effects without observed combined cytotoxicity. These results suggest their potential for further research and clinical trials in combating enterovirus infections.","PeriodicalId":7205,"journal":{"name":"Acta virologica","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140976398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Niloofar Farsiu, Abozar Ghorbani, Thomas P. Karbanowicz, Negar Mottaghi-Dastjerdi, Pierangelo Veltri, P. Guzzi
Long non-coding RNAs (lncRNAs) have gained prominence due to their involvement in various cellular processes, but their specific roles remain elusive. Dysregulation of lncRNAs has been implicated in the pathogenesis of several diseases. In this study, we aimed to shed light on the role of lncRNAs in individuals infected with human immunodeficiency virus type 1 (HIV-1) by examining their changes in the expression patterns related to the initiation of antiretroviral therapy (ART) during acute or chronic phases of infection, compared to healthy controls. We found 316 differentially expressed (DE) lncRNAs in patients receiving long-term ART, shedding light on their potential roles. We also observed interactions between these DE lncRNAs and specific microRNAs (miRNAs). Some of these miRNAs, such as hsa-miR-574-5p, hsa-miR-765, hsa-miR-6165, hsa-miR-1207-5p, and hsa-miR-378i, are associated with cancer progression or suppression, while others, including hsa-miR-328-5p, hsa-miR-4753-3p, and MiR-664, play roles in immune system regulation. Furthermore, our study revealed substantial enrichment in distinct Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, such as axon guidance, PI3K-Akt signaling, and MAPK signaling pathways. Although our results indicate possible molecular processes impacted by the discovered lncRNAs, we cannot explicitly establish causality or specific connections between lncRNAs and genes in these pathways, fostering more specific studies. Furthermore, Gene Ontology (GO) analysis highlighted terms such as cytoskeletal protein binding, ion channel function, synaptic processes, neuron projection, and the somatodendritic compartment, underscoring the relevance of lncRNAs in these cellular components within the context of HIV-1 infection and ART treatment. In conclusion, our study emphasizes the need for further exploration of lncRNAs as potential biomarkers and therapeutic targets in HIV-1-infected patients, with a particular focus on CD4+ T cells. Understanding the functions of lncRNAs in these contexts may pave the way for novel treatment strategies and improved patient outcomes, aligning with the broader goals of our research.
{"title":"Discovery of long non-coding RNAs in naïve CD4+ T cells in response to initiating antiretroviral therapy at acute or chronic phase of HIV-1 infection","authors":"Niloofar Farsiu, Abozar Ghorbani, Thomas P. Karbanowicz, Negar Mottaghi-Dastjerdi, Pierangelo Veltri, P. Guzzi","doi":"10.3389/av.2024.11572","DOIUrl":"https://doi.org/10.3389/av.2024.11572","url":null,"abstract":"Long non-coding RNAs (lncRNAs) have gained prominence due to their involvement in various cellular processes, but their specific roles remain elusive. Dysregulation of lncRNAs has been implicated in the pathogenesis of several diseases. In this study, we aimed to shed light on the role of lncRNAs in individuals infected with human immunodeficiency virus type 1 (HIV-1) by examining their changes in the expression patterns related to the initiation of antiretroviral therapy (ART) during acute or chronic phases of infection, compared to healthy controls. We found 316 differentially expressed (DE) lncRNAs in patients receiving long-term ART, shedding light on their potential roles. We also observed interactions between these DE lncRNAs and specific microRNAs (miRNAs). Some of these miRNAs, such as hsa-miR-574-5p, hsa-miR-765, hsa-miR-6165, hsa-miR-1207-5p, and hsa-miR-378i, are associated with cancer progression or suppression, while others, including hsa-miR-328-5p, hsa-miR-4753-3p, and MiR-664, play roles in immune system regulation. Furthermore, our study revealed substantial enrichment in distinct Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, such as axon guidance, PI3K-Akt signaling, and MAPK signaling pathways. Although our results indicate possible molecular processes impacted by the discovered lncRNAs, we cannot explicitly establish causality or specific connections between lncRNAs and genes in these pathways, fostering more specific studies. Furthermore, Gene Ontology (GO) analysis highlighted terms such as cytoskeletal protein binding, ion channel function, synaptic processes, neuron projection, and the somatodendritic compartment, underscoring the relevance of lncRNAs in these cellular components within the context of HIV-1 infection and ART treatment. In conclusion, our study emphasizes the need for further exploration of lncRNAs as potential biomarkers and therapeutic targets in HIV-1-infected patients, with a particular focus on CD4+ T cells. Understanding the functions of lncRNAs in these contexts may pave the way for novel treatment strategies and improved patient outcomes, aligning with the broader goals of our research.","PeriodicalId":7205,"journal":{"name":"Acta virologica","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140714475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Humankind has witnessed increased frequency of emerging and re-emerging viral diseases in the past few decades. The major categories of pathogenic emerging and re-emerging viral infections include respiratory, arthropod-borne and bat-borne zoonotic viruses. These viral infections are notorious for causing immune dysregulation and have the potential to mount excessive immune reaction, causing immunopathology that includes tissue injury, systemic inflammation, multi-organ failure and even death. A better understanding of the emerging or re-emerging viral-mediated immunomodulation is necessary for controlling the virus, while preventing severity of the disease associated with exaggerated immune response. In this article, we review the current understanding of emerging and re-emerging respiratory, arboviral and bat-borne zoonotic viruses; and consequent immune dysregulation or immunopathology associated with these viral infections.
{"title":"Immunopathology of emerging and re-emerging viral infections: an updated overview","authors":"Dimpu Gogoi, Pranjal Jyoti Baruah, Kanwar Narain","doi":"10.3389/av.2024.12108","DOIUrl":"https://doi.org/10.3389/av.2024.12108","url":null,"abstract":"Humankind has witnessed increased frequency of emerging and re-emerging viral diseases in the past few decades. The major categories of pathogenic emerging and re-emerging viral infections include respiratory, arthropod-borne and bat-borne zoonotic viruses. These viral infections are notorious for causing immune dysregulation and have the potential to mount excessive immune reaction, causing immunopathology that includes tissue injury, systemic inflammation, multi-organ failure and even death. A better understanding of the emerging or re-emerging viral-mediated immunomodulation is necessary for controlling the virus, while preventing severity of the disease associated with exaggerated immune response. In this article, we review the current understanding of emerging and re-emerging respiratory, arboviral and bat-borne zoonotic viruses; and consequent immune dysregulation or immunopathology associated with these viral infections.","PeriodicalId":7205,"journal":{"name":"Acta virologica","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140727803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mariana F. Campos, Larissa E. C. Constant, D. E. Teixeira, Rodrigo P. Silva-Aguiar, Patrícia R. M. Rocco, Ronaldo Mohana-Borges, Gilda G. Leitão, Celso Caruso-Neves, Suzana G. Leitão, D. Allonso
Coronavirus Disease 2019 (COVID-19) pandemic led to 7 million deaths and more than 770 million confirmed cases worldwide. The Spike glycoprotein (SP) is responsible for recognizing and binding to angiotensin converting enzyme-2 (ACE-2) in the host cell membrane and seems to modulate host cellular signaling pathways. Here, we investigate the effects of SP (stabilized in prefusion conformation) in human umbilical vein endothelial cells (HUVEC-C) lineage on the ACE-2 expression profile and in cell glucose metabolism. Our data indicate that SP binds to ACE-2, is internalized by HUVEC-C cells, and positively modulates ACE-2 expression. In addition, SP alone induces a transient increase in glucose uptake and a decrease in lactate production, characterizing itself as a metabolic regulating protein. The present study is the first to demonstrate that SP induces a slight change in cell metabolism, promotes the overexpression of ACE-2 and its increased availability in the membrane of endothelial cells in a time-dependent fashion.
{"title":"SARS-CoV-2 spike protein increases angiotensin converting enzyme-2 expression and promotes an increase in glucose uptake in endothelial cells","authors":"Mariana F. Campos, Larissa E. C. Constant, D. E. Teixeira, Rodrigo P. Silva-Aguiar, Patrícia R. M. Rocco, Ronaldo Mohana-Borges, Gilda G. Leitão, Celso Caruso-Neves, Suzana G. Leitão, D. Allonso","doi":"10.3389/av.2024.12136","DOIUrl":"https://doi.org/10.3389/av.2024.12136","url":null,"abstract":"Coronavirus Disease 2019 (COVID-19) pandemic led to 7 million deaths and more than 770 million confirmed cases worldwide. The Spike glycoprotein (SP) is responsible for recognizing and binding to angiotensin converting enzyme-2 (ACE-2) in the host cell membrane and seems to modulate host cellular signaling pathways. Here, we investigate the effects of SP (stabilized in prefusion conformation) in human umbilical vein endothelial cells (HUVEC-C) lineage on the ACE-2 expression profile and in cell glucose metabolism. Our data indicate that SP binds to ACE-2, is internalized by HUVEC-C cells, and positively modulates ACE-2 expression. In addition, SP alone induces a transient increase in glucose uptake and a decrease in lactate production, characterizing itself as a metabolic regulating protein. The present study is the first to demonstrate that SP induces a slight change in cell metabolism, promotes the overexpression of ACE-2 and its increased availability in the membrane of endothelial cells in a time-dependent fashion.","PeriodicalId":7205,"journal":{"name":"Acta virologica","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140265727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Influenza A viruses are enveloped viruses with a genome of eight single-stranded negative-sense RNA molecules. In virions, RNA segments are found as vRNPs associated with NP proteins. The RdRp enzyme, which catalyzes the replication/transcription of the viral genome, is carried as attached to vRNPs. In this study, it was demonstrated that the PA subunit of the viral RdRp interacts with β-actin proteins by the yeast two-hybrid assay. It was shown that the amino-terminal domains of the β-actin protein bind to the carboxy-terminal moiety of the viral PA protein in the mammalian cells. The results were supported by in silico analysis. Over-expression of the β-actin protein was found to have a negative effect on the viral RdRp activity in mini-replicon, but its mechanism of action has remained unknown. The results suggest that the interaction of β-actin and PA protein, a component of vRNPs, may have a role in the intracellular trafficking of the influenza vRNPs and/or viral transcription.
甲型流感病毒是一种包膜病毒，基因组由八条单链负义 RNA 分子组成。在病毒中，RNA片段以与NP蛋白相关联的vRNP形式存在。催化病毒基因组复制/转录的 RdRp 酶附着在 vRNPs 上。本研究通过酵母双杂交实验证明，病毒 RdRp 的 PA 亚基与 β-actin 蛋白相互作用。在哺乳动物细胞中，β-肌动蛋白的氨基末端与病毒 PA 蛋白的羧基末端结合。这一结果得到了硅学分析的支持。研究发现，β-肌动蛋白的过度表达对迷你复制子中病毒 RdRp 的活性有负面影响，但其作用机制仍不清楚。研究结果表明，β-肌动蛋白与 vRNPs 的组成部分 PA 蛋白的相互作用可能在流感 vRNPs 的细胞内运输和/或病毒转录中发挥作用。
{"title":"The interaction of influenza A virus RNA polymerase PA subunit with the human β-actin protein","authors":"Nazife Gelmez, E. Çağlayan, K. Turan","doi":"10.3389/av.2023.11890","DOIUrl":"https://doi.org/10.3389/av.2023.11890","url":null,"abstract":"Influenza A viruses are enveloped viruses with a genome of eight single-stranded negative-sense RNA molecules. In virions, RNA segments are found as vRNPs associated with NP proteins. The RdRp enzyme, which catalyzes the replication/transcription of the viral genome, is carried as attached to vRNPs. In this study, it was demonstrated that the PA subunit of the viral RdRp interacts with β-actin proteins by the yeast two-hybrid assay. It was shown that the amino-terminal domains of the β-actin protein bind to the carboxy-terminal moiety of the viral PA protein in the mammalian cells. The results were supported by in silico analysis. Over-expression of the β-actin protein was found to have a negative effect on the viral RdRp activity in mini-replicon, but its mechanism of action has remained unknown. The results suggest that the interaction of β-actin and PA protein, a component of vRNPs, may have a role in the intracellular trafficking of the influenza vRNPs and/or viral transcription.","PeriodicalId":7205,"journal":{"name":"Acta virologica","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139445490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Human adenovirus-5 (hAd5) is an important gene delivery vector, which has been widely used in various fields of biomedicine, such as gene therapy, cancer therapy, and vaccine development. However, replication-competent adenovirus (RCA) generated when adenoviral vectors are prepared in HEK293 cells has remained a concern. In this study, the human adenovirus-5 was modified to shorten the length of homologous sequence between the adenovirus and HEK293 genomic DNA, thereby reducing the production of RCA. The recombinant hAd5 was amplified and serially passaged 12 times in HEK293 cells. The amounts of RCA at passage 2, 4, 6, 8, 10, and 12 were detected by quantitative real-time PCR. The results demonstrated that the modification of adenoviral vector could effectively reduce the production of RCA during serial passages in HEK293 cells.
{"title":"Construction of recombinant adenovirus-5 vector to prevent replication-competent adenovirus occurrence","authors":"Wenbo Xie, Yifei Yuan, Bo Liu, Min Liang","doi":"10.3389/av.2023.11642","DOIUrl":"https://doi.org/10.3389/av.2023.11642","url":null,"abstract":"Human adenovirus-5 (hAd5) is an important gene delivery vector, which has been widely used in various fields of biomedicine, such as gene therapy, cancer therapy, and vaccine development. However, replication-competent adenovirus (RCA) generated when adenoviral vectors are prepared in HEK293 cells has remained a concern. In this study, the human adenovirus-5 was modified to shorten the length of homologous sequence between the adenovirus and HEK293 genomic DNA, thereby reducing the production of RCA. The recombinant hAd5 was amplified and serially passaged 12 times in HEK293 cells. The amounts of RCA at passage 2, 4, 6, 8, 10, and 12 were detected by quantitative real-time PCR. The results demonstrated that the modification of adenoviral vector could effectively reduce the production of RCA during serial passages in HEK293 cells.","PeriodicalId":7205,"journal":{"name":"Acta virologica","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138962631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Based on the crystal structure of the 3C-like protease/Nsp5 (PDB ID 6W63), virtual hits were screened from a natural product compounds database—containing 407270 natural products—by using the high-throughput virtual screening (HTVS) module of Discovery Studio software, and then filtering by “Lipinski’s rule of five” from the top 20 virtual hits. Two star-hits were selected by CDOCKER results and the protein-ligand interactions with the 3CLpro were analyzed. Finally, a 100 ns molecular dynamics simulation was carried out to verify the stability of the receptor-ligand complexes. We screened potent broad-spectrum non-covalent inhibitors that could bind to the SARS-CoV-2 3CLpro active binding site from the natural product compounds library through HTVS and molecular dynamics simulations methods. The LibDock scores and -CDOCKER energy value of the star-hits were higher than the original ligands (X77) bound to 3CLpro. CNP0348829 and CNP0474002, as star-hits, can bind stably to the active site of 3CLpro, which are promising candidate compounds for the treatment of SARS-CoV-2 and provide a theoretical basis for the development of antiviral drugs. The results of the present study may be useful in the prevention and therapeutic perspectives of COVID-19. However, further in vitro and in vivo validation tests are required in the future.
{"title":"Virtual screening and molecular dynamics simulation to identify potential SARS-CoV-2 3CLpro inhibitors from a natural product compounds library","authors":"Chunchun Gan, Xiaopu Jia, Shuai Fan, Shuqing Wang, Weikai Jing, Xiaopeng Wei","doi":"10.3389/av.2023.12464","DOIUrl":"https://doi.org/10.3389/av.2023.12464","url":null,"abstract":"Based on the crystal structure of the 3C-like protease/Nsp5 (PDB ID 6W63), virtual hits were screened from a natural product compounds database—containing 407270 natural products—by using the high-throughput virtual screening (HTVS) module of Discovery Studio software, and then filtering by “Lipinski’s rule of five” from the top 20 virtual hits. Two star-hits were selected by CDOCKER results and the protein-ligand interactions with the 3CLpro were analyzed. Finally, a 100 ns molecular dynamics simulation was carried out to verify the stability of the receptor-ligand complexes. We screened potent broad-spectrum non-covalent inhibitors that could bind to the SARS-CoV-2 3CLpro active binding site from the natural product compounds library through HTVS and molecular dynamics simulations methods. The LibDock scores and -CDOCKER energy value of the star-hits were higher than the original ligands (X77) bound to 3CLpro. CNP0348829 and CNP0474002, as star-hits, can bind stably to the active site of 3CLpro, which are promising candidate compounds for the treatment of SARS-CoV-2 and provide a theoretical basis for the development of antiviral drugs. The results of the present study may be useful in the prevention and therapeutic perspectives of COVID-19. However, further in vitro and in vivo validation tests are required in the future.","PeriodicalId":7205,"journal":{"name":"Acta virologica","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2023-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138999298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
TRK-fused gene (TFG, tropomyosin-receptor kinase fused gene) is known to negatively regulate the retinoic acid inducible gene (RIG)-I-like receptor (RLR)-mediated interferon (IFN)-I pathway in human cells, thereby participating in the paramyxovirus infection process. We showed that pigeon paramyxovirus type 1 (PPMV-1) infection significantly upregulates TFG expression in infected cells at an early stage. We speculated that PPMV-1 would inhibit IFN activation by upregulating a negative regulator of the IFN pathway. This hypothesis was proved when TFG protein expression was knocked down by RNAi and the replication level of PPMV-1 virus decreased, which indicated that TFG upregulation in the early infection stage benefit virus replication. We next used the IFN-β promoter reporter system to evaluate the role of the TFG in the IFN pathway. The results showed that the TFG inhibited the IFN-β expression stimulated by RIG-I, MAVS (mitochondrial antiviral signaling protein) and TANK-binding kinase 1 (TBK1), but did not inhibit IFN-β activated by the interferon regulatory transcription factor 3 (IRF3), indicating that TFG may affect the function of TBK1, which play an important role in phosphorylation of the IRF3. Further experiments showed that the TFG inhibited the phosphorylation of TBK1, resulting in IRF3 being unable to be phosphorylated. Subsequent experiments on IFN pathway activation confirmed that the IRF3 phosphorylation level was significantly downregulated after overexpression of TFG, while the IFN-β promoter reporting experiment showed that TFG did not directly inhibit the IFN response activated by IRF3. This confirmed that TFG protein negatively regulates the IFN-β pathway by inhibiting TBK1 phosphorylation.
{"title":"The TRK-fused gene negatively regulates interferon signaling by inhibiting TBK1 phosphorylation during PPMV-1 infection","authors":"Ye Tian, Ruixue Xue, Cuilian Yu, Liping Liu, Shumin Chen, Junfeng Lv","doi":"10.3389/av.2023.11607","DOIUrl":"https://doi.org/10.3389/av.2023.11607","url":null,"abstract":"TRK-fused gene (TFG, tropomyosin-receptor kinase fused gene) is known to negatively regulate the retinoic acid inducible gene (RIG)-I-like receptor (RLR)-mediated interferon (IFN)-I pathway in human cells, thereby participating in the paramyxovirus infection process. We showed that pigeon paramyxovirus type 1 (PPMV-1) infection significantly upregulates TFG expression in infected cells at an early stage. We speculated that PPMV-1 would inhibit IFN activation by upregulating a negative regulator of the IFN pathway. This hypothesis was proved when TFG protein expression was knocked down by RNAi and the replication level of PPMV-1 virus decreased, which indicated that TFG upregulation in the early infection stage benefit virus replication. We next used the IFN-β promoter reporter system to evaluate the role of the TFG in the IFN pathway. The results showed that the TFG inhibited the IFN-β expression stimulated by RIG-I, MAVS (mitochondrial antiviral signaling protein) and TANK-binding kinase 1 (TBK1), but did not inhibit IFN-β activated by the interferon regulatory transcription factor 3 (IRF3), indicating that TFG may affect the function of TBK1, which play an important role in phosphorylation of the IRF3. Further experiments showed that the TFG inhibited the phosphorylation of TBK1, resulting in IRF3 being unable to be phosphorylated. Subsequent experiments on IFN pathway activation confirmed that the IRF3 phosphorylation level was significantly downregulated after overexpression of TFG, while the IFN-β promoter reporting experiment showed that TFG did not directly inhibit the IFN response activated by IRF3. This confirmed that TFG protein negatively regulates the IFN-β pathway by inhibiting TBK1 phosphorylation.","PeriodicalId":7205,"journal":{"name":"Acta virologica","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135869156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Despite the urgent need for effective antivirals against SARS-CoV-2 to mitigate the catastrophic impact of the COVID-19 pandemic, favipiravir and ivermectin are among the common repurposed drugs that have been provisionally used in some countries. There have been clinical trials with mixed results, and therefore, it is still inconclusive whether they are effective or should be dismissed. It is plausible that the lack of clear-cut clinical benefits was due to the finding of only marginal levels of in vivo antiviral activity. An obvious way to improve the activity of antivirals is to use them in synergistic combinations. The in vitro antiviral activity of the combinations of favipiravir, ivermectin, niclosamide, and chloroquine against SARS-CoV-2 was assessed in Vero E6 cells and the lung epithelial cell, Calu-3. Here we show that favipiravir and ivermectin had synergistic effects against SARS-CoV-2 in Vero E6 cells. In addition, we found that favipiravir had an additive effect with niclosamide, another repurposed anti-parasitic drug with anti-SARS-CoV-2 activity. However, the anti-SARS-CoV-2 activity of favipiravir was drastically reduced when evaluated in Calu-3 cells. This suggested that this cell type might not be able to metabolize favipiravir into its active form and that this deficiency in some cell types may affect the in vivo efficacy of this drug. Favipiravir and ivermectin show the best synergistic effect. This combination is being tested in a randomized controlled clinical trial (NCT05155527).
{"title":"Favipiravir and ivermectin show in vitro synergistic antiviral activity against SARS-CoV-2","authors":"Kunlakanya Jitobaom, Chompunuch Boonarkart, Suwimon Manopwisedjaroen, Nuntaya Punyadee, Suparerk Borwornpinyo, Arunee Thitithanyanont, Panisadee Avirutnan, Prasert Auewarakul","doi":"10.3389/av.2023.12265","DOIUrl":"https://doi.org/10.3389/av.2023.12265","url":null,"abstract":"Despite the urgent need for effective antivirals against SARS-CoV-2 to mitigate the catastrophic impact of the COVID-19 pandemic, favipiravir and ivermectin are among the common repurposed drugs that have been provisionally used in some countries. There have been clinical trials with mixed results, and therefore, it is still inconclusive whether they are effective or should be dismissed. It is plausible that the lack of clear-cut clinical benefits was due to the finding of only marginal levels of in vivo antiviral activity. An obvious way to improve the activity of antivirals is to use them in synergistic combinations. The in vitro antiviral activity of the combinations of favipiravir, ivermectin, niclosamide, and chloroquine against SARS-CoV-2 was assessed in Vero E6 cells and the lung epithelial cell, Calu-3. Here we show that favipiravir and ivermectin had synergistic effects against SARS-CoV-2 in Vero E6 cells. In addition, we found that favipiravir had an additive effect with niclosamide, another repurposed anti-parasitic drug with anti-SARS-CoV-2 activity. However, the anti-SARS-CoV-2 activity of favipiravir was drastically reduced when evaluated in Calu-3 cells. This suggested that this cell type might not be able to metabolize favipiravir into its active form and that this deficiency in some cell types may affect the in vivo efficacy of this drug. Favipiravir and ivermectin show the best synergistic effect. This combination is being tested in a randomized controlled clinical trial (NCT05155527).","PeriodicalId":7205,"journal":{"name":"Acta virologica","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135934155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dongjin Choi, Megha Rai, Amit Rai, Mami Yamazaki, Yoonsoo Hahn
The genus Potyvirus (the family Potyviridae ) is the largest group of plant-infecting viruses transmitted by aphids. Through high-throughput RNA sequencing analysis of asymptomatic samples of Aconitum carmichaelii , a significant medicinal herb in Asia, we identified the genome sequences of two RNA viruses, tentatively named Aconitum potyvirus 1 (AcoPV1) and Aconitum potyvirus 2 (AcoPV2). The genomes of AcoPV1 and AcoPV2 encode polyproteins composed of 3,069 and 3,054 amino acids, respectively. Sequence comparisons and phylogenetic analyses established that AcoPV1 and AcoPV2 represent unique, novel members within the genus Potyvirus . The estimated RNA polymerase slippage rates at the GAAAAAA motif, responsible for the production of P3N-PIPO or P3N-ALT trans-frame fusion proteins, were 0.79% in AcoPV1 and 1.38% in AcoPV2. The RNA reads of AcoPV1 and AcoPV2 were predominantly found in the leaf and flower tissues, indicating potential feeding preferences of vectors for these viruses. These findings demonstrate the effectiveness of high-throughput RNA sequencing in not only uncovering novel potyviruses, but also in elucidating their genomic dynamics within host plants.
{"title":"Discovery of two novel potyvirus genome sequences by high-throughput RNA sequencing in Aconitum carmichaelii tissue samples","authors":"Dongjin Choi, Megha Rai, Amit Rai, Mami Yamazaki, Yoonsoo Hahn","doi":"10.3389/av.2023.11782","DOIUrl":"https://doi.org/10.3389/av.2023.11782","url":null,"abstract":"The genus Potyvirus (the family Potyviridae ) is the largest group of plant-infecting viruses transmitted by aphids. Through high-throughput RNA sequencing analysis of asymptomatic samples of Aconitum carmichaelii , a significant medicinal herb in Asia, we identified the genome sequences of two RNA viruses, tentatively named Aconitum potyvirus 1 (AcoPV1) and Aconitum potyvirus 2 (AcoPV2). The genomes of AcoPV1 and AcoPV2 encode polyproteins composed of 3,069 and 3,054 amino acids, respectively. Sequence comparisons and phylogenetic analyses established that AcoPV1 and AcoPV2 represent unique, novel members within the genus Potyvirus . The estimated RNA polymerase slippage rates at the GAAAAAA motif, responsible for the production of P3N-PIPO or P3N-ALT trans-frame fusion proteins, were 0.79% in AcoPV1 and 1.38% in AcoPV2. The RNA reads of AcoPV1 and AcoPV2 were predominantly found in the leaf and flower tissues, indicating potential feeding preferences of vectors for these viruses. These findings demonstrate the effectiveness of high-throughput RNA sequencing in not only uncovering novel potyviruses, but also in elucidating their genomic dynamics within host plants.","PeriodicalId":7205,"journal":{"name":"Acta virologica","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135968977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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