Kenya DeBarros, Mahfuz Khan, Morgan Coleman, Vincent C. Bond, Virginia Floyd, Erick Gbodossou, Amad Diop, Lauren R. H. Krumpe, Barry R. O’Keefe, Michael D. Powell
MoMo30 is an antiviral protein isolated from aqueous extracts of Momordica balsamina L. (Senegalese bitter melon). Previously, we demonstrated MoMo30’s antiviral activity against HIV-1. Here, we explore whether MoMo30 has antiviral activity against the COVID-19 virus, SARS-CoV-2. MLV particles pseudotyped with the SARS-CoV-2 Spike glycoprotein and a Luciferase reporter gene (SARS2-PsV) were developed from a three-way co-transfection of HEK293-T17 cells. MoMo30’s inhibition of SARS2-PsV infection was measured using a luciferase assay and its cytotoxicity using an XTT assay. Additionally, MoMo30’s interactions with the variants and domains of Spike were determined by ELISA. We show that MoMo30 inhibits SARS2-PsV infection. We also report evidence of the direct interaction of MoMo30 and SARS-CoV-2 Spike from WH-1, Alpha, Delta, and Omicron variants. Furthermore, MoMo30 interacts with both the S1 and S2 domains of Spike but not the receptor binding domain (RBD), suggesting that MoMo30 inhibits SARS-CoV-2 infection by inhibiting fusion of the virus and the host cell via interactions with Spike.
{"title":"MoMo30 Binds to SARS-CoV-2 Spike Variants and Blocks Infection by SARS-CoV-2 Pseudovirus","authors":"Kenya DeBarros, Mahfuz Khan, Morgan Coleman, Vincent C. Bond, Virginia Floyd, Erick Gbodossou, Amad Diop, Lauren R. H. Krumpe, Barry R. O’Keefe, Michael D. Powell","doi":"10.3390/v16091433","DOIUrl":"https://doi.org/10.3390/v16091433","url":null,"abstract":"MoMo30 is an antiviral protein isolated from aqueous extracts of Momordica balsamina L. (Senegalese bitter melon). Previously, we demonstrated MoMo30’s antiviral activity against HIV-1. Here, we explore whether MoMo30 has antiviral activity against the COVID-19 virus, SARS-CoV-2. MLV particles pseudotyped with the SARS-CoV-2 Spike glycoprotein and a Luciferase reporter gene (SARS2-PsV) were developed from a three-way co-transfection of HEK293-T17 cells. MoMo30’s inhibition of SARS2-PsV infection was measured using a luciferase assay and its cytotoxicity using an XTT assay. Additionally, MoMo30’s interactions with the variants and domains of Spike were determined by ELISA. We show that MoMo30 inhibits SARS2-PsV infection. We also report evidence of the direct interaction of MoMo30 and SARS-CoV-2 Spike from WH-1, Alpha, Delta, and Omicron variants. Furthermore, MoMo30 interacts with both the S1 and S2 domains of Spike but not the receptor binding domain (RBD), suggesting that MoMo30 inhibits SARS-CoV-2 infection by inhibiting fusion of the virus and the host cell via interactions with Spike.","PeriodicalId":501326,"journal":{"name":"Viruses","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142206897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Daniele Armenia, Luca Carioti, Valeria Micheli, Isabella Bon, Tiziano Allice, Celestino Bonura, Bianca Bruzzone, Fiorenza Bracchitta, Francesco Cerutti, Giovanni Maurizio Giammanco, Federica Stefanelli, Maria Addolorata Bonifacio, Ada Bertoli, Marialinda Vatteroni, Gabriele Ibba, Federica Novazzi, Maria Rosaria Lipsi, Nunzia Cuomo, Ilaria Vicenti, Francesca Ceccherini-Silberstein, Barbara Rossetti, Antonia Bezenchek, Francesco Saladini, Maurizio Zazzi, Maria Mercedes Santoro
Background: Next-generation sequencing (NGS) is gradually replacing Sanger sequencing for HIV genotypic drug resistance testing (GRT). This work evaluated the concordance among different NGS-GRT interpretation tools in a real-life setting. Methods: Routine NGS-GRT data were generated from viral RNA at 11 Italian laboratories with the AD4SEQ HIV-1 Solution v2 commercial kit. NGS results were interpreted by the SmartVir system provided by the kit and by two online tools (HyDRA Web and Stanford HIVdb). NGS-GRT was considered valid when the coverage was >100 reads (100×) at each PR/RT/IN resistance-associated position listed in the HIVdb 9.5.1 algorithm. Results: Among 629 NGS-GRT, 75.2%, 74.2%, and 70.9% were valid according to SmartVir, HyDRA Web, and HIVdb. Considering at least two interpretation tools, 463 (73.6%) NGS-GRT had a valid coverage for resistance analyses. The proportion of valid samples was affected by viremia <10,000–1000 copies/mL and non-B subtypes. Mutations at an NGS frequency >10% showed fair concordance among different interpretation tools. Conclusion: This Italian survey on NGS resistance testing suggests that viremia levels and HIV subtype affect NGS-GRT coverage. Within the current routine method for NGS-GRT, only mutations with frequency >10% seem reliably detected across different interpretation tools.
{"title":"Comparison of Different HIV-1 Resistance Interpretation Tools for Next-Generation Sequencing in Italy","authors":"Daniele Armenia, Luca Carioti, Valeria Micheli, Isabella Bon, Tiziano Allice, Celestino Bonura, Bianca Bruzzone, Fiorenza Bracchitta, Francesco Cerutti, Giovanni Maurizio Giammanco, Federica Stefanelli, Maria Addolorata Bonifacio, Ada Bertoli, Marialinda Vatteroni, Gabriele Ibba, Federica Novazzi, Maria Rosaria Lipsi, Nunzia Cuomo, Ilaria Vicenti, Francesca Ceccherini-Silberstein, Barbara Rossetti, Antonia Bezenchek, Francesco Saladini, Maurizio Zazzi, Maria Mercedes Santoro","doi":"10.3390/v16091422","DOIUrl":"https://doi.org/10.3390/v16091422","url":null,"abstract":"Background: Next-generation sequencing (NGS) is gradually replacing Sanger sequencing for HIV genotypic drug resistance testing (GRT). This work evaluated the concordance among different NGS-GRT interpretation tools in a real-life setting. Methods: Routine NGS-GRT data were generated from viral RNA at 11 Italian laboratories with the AD4SEQ HIV-1 Solution v2 commercial kit. NGS results were interpreted by the SmartVir system provided by the kit and by two online tools (HyDRA Web and Stanford HIVdb). NGS-GRT was considered valid when the coverage was >100 reads (100×) at each PR/RT/IN resistance-associated position listed in the HIVdb 9.5.1 algorithm. Results: Among 629 NGS-GRT, 75.2%, 74.2%, and 70.9% were valid according to SmartVir, HyDRA Web, and HIVdb. Considering at least two interpretation tools, 463 (73.6%) NGS-GRT had a valid coverage for resistance analyses. The proportion of valid samples was affected by viremia <10,000–1000 copies/mL and non-B subtypes. Mutations at an NGS frequency >10% showed fair concordance among different interpretation tools. Conclusion: This Italian survey on NGS resistance testing suggests that viremia levels and HIV subtype affect NGS-GRT coverage. Within the current routine method for NGS-GRT, only mutations with frequency >10% seem reliably detected across different interpretation tools.","PeriodicalId":501326,"journal":{"name":"Viruses","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142206896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shulin Cao, Xiaoyue Yang, Lele Xia, Xing Zhang, Haiyan Sun, Yuanyu Deng, Yan Shu, Aixiang Zhang, Huaigu Chen, Wei Li
Fusarium head blight (FHB), a disease inflicted by Fusarium graminearum and F. asiaticum, poses a growing threat to wheat in China, particularly in the face of climate change and evolving agricultural practices. This study unveiled the discovery of the victorivirus FgVV2 from the F. asiaticum strain F16176 and comprehensively characterized the function of the two victoriviruses FaVV1 and FaVV2 in virulence. Through comparative analysis with a virus-free strain, we established that these mycoviruses markedly repress the sexual reproduction and pathogenicity of their fungal hosts. Furthermore, we synthesized the coat protein (CP) genes CP1 from FaVV1 and CP2 from FaVV2, which were fused with the green fluorescent protein (GFP) gene and successfully expressed in Fusarium strains in wild-type isolates of F. asiaticum and F. graminearum. Similar to virus-infected strains, the transformed strains expressing CPs showed a significant decrease in perithecia formation and pathogenicity. Notably, CP2 exhibited a stronger inhibitory effect than CP1, yet the suppression of sexual reproduction in F. graminearum was less pronounced than that in F. asiaticum. Additionally, the pathogenicity of the F. asiaticum and F. graminearum strains expressing CP1 or CP2 was substantially diminished against wheat heads. The GFP-tagged CP1 and CP2 revealed distinct cellular localization patterns, suggesting various mechanisms of interaction with the host. The findings of this study provide a significant research foundation for the study of the interaction mechanisms between FaVV1 and FaVV2 with their hosts, as well as for the exploration and utilization of fungal viral resources.
{"title":"Coat Proteins of the Novel Victoriviruses FaVV1 and FaVV2 Suppress Sexual Reproduction and Virulence in the Pathogen of Fusarium Head Blight","authors":"Shulin Cao, Xiaoyue Yang, Lele Xia, Xing Zhang, Haiyan Sun, Yuanyu Deng, Yan Shu, Aixiang Zhang, Huaigu Chen, Wei Li","doi":"10.3390/v16091424","DOIUrl":"https://doi.org/10.3390/v16091424","url":null,"abstract":"Fusarium head blight (FHB), a disease inflicted by Fusarium graminearum and F. asiaticum, poses a growing threat to wheat in China, particularly in the face of climate change and evolving agricultural practices. This study unveiled the discovery of the victorivirus FgVV2 from the F. asiaticum strain F16176 and comprehensively characterized the function of the two victoriviruses FaVV1 and FaVV2 in virulence. Through comparative analysis with a virus-free strain, we established that these mycoviruses markedly repress the sexual reproduction and pathogenicity of their fungal hosts. Furthermore, we synthesized the coat protein (CP) genes CP1 from FaVV1 and CP2 from FaVV2, which were fused with the green fluorescent protein (GFP) gene and successfully expressed in Fusarium strains in wild-type isolates of F. asiaticum and F. graminearum. Similar to virus-infected strains, the transformed strains expressing CPs showed a significant decrease in perithecia formation and pathogenicity. Notably, CP2 exhibited a stronger inhibitory effect than CP1, yet the suppression of sexual reproduction in F. graminearum was less pronounced than that in F. asiaticum. Additionally, the pathogenicity of the F. asiaticum and F. graminearum strains expressing CP1 or CP2 was substantially diminished against wheat heads. The GFP-tagged CP1 and CP2 revealed distinct cellular localization patterns, suggesting various mechanisms of interaction with the host. The findings of this study provide a significant research foundation for the study of the interaction mechanisms between FaVV1 and FaVV2 with their hosts, as well as for the exploration and utilization of fungal viral resources.","PeriodicalId":501326,"journal":{"name":"Viruses","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142206895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Federico Vello, Francesco Filippini, Irene Righetto
Computer-aided analysis of proteins or nucleic acids seems like a matter of course nowadays; however, the history of Bioinformatics and Computational Biology is quite recent. The advent of high-throughput sequencing has led to the production of “big data”, which has also affected the field of virology. The collaboration between the communities of bioinformaticians and virologists already started a few decades ago and it was strongly enhanced by the recent SARS-CoV-2 pandemics. In this article, which is the first in a series on how bioinformatics can enhance virus research, we show that highly useful information is retrievable from selected general and dedicated databases. Indeed, an enormous amount of information—both in terms of nucleotide/protein sequences and their annotation—is deposited in the general databases of international organisations participating in the International Nucleotide Sequence Database Collaboration (INSDC). However, more and more virus-specific databases have been established and are progressively enriched with the contents and features reported in this article. Since viruses are intracellular obligate parasites, a special focus is given to host-pathogen protein-protein interaction databases. Finally, we illustrate several phylogenetic and phylodynamic tools, combining information on algorithms and features with practical information on how to use them and case studies that validate their usefulness. Databases and tools for functional inference will be covered in the next article of this series: Bioinformatics goes viral: II. Sequence-based and structure-based functional analyses for boosting virus research.
{"title":"Bioinformatics Goes Viral: I. Databases, Phylogenetics and Phylodynamics Tools for Boosting Virus Research","authors":"Federico Vello, Francesco Filippini, Irene Righetto","doi":"10.3390/v16091425","DOIUrl":"https://doi.org/10.3390/v16091425","url":null,"abstract":"Computer-aided analysis of proteins or nucleic acids seems like a matter of course nowadays; however, the history of Bioinformatics and Computational Biology is quite recent. The advent of high-throughput sequencing has led to the production of “big data”, which has also affected the field of virology. The collaboration between the communities of bioinformaticians and virologists already started a few decades ago and it was strongly enhanced by the recent SARS-CoV-2 pandemics. In this article, which is the first in a series on how bioinformatics can enhance virus research, we show that highly useful information is retrievable from selected general and dedicated databases. Indeed, an enormous amount of information—both in terms of nucleotide/protein sequences and their annotation—is deposited in the general databases of international organisations participating in the International Nucleotide Sequence Database Collaboration (INSDC). However, more and more virus-specific databases have been established and are progressively enriched with the contents and features reported in this article. Since viruses are intracellular obligate parasites, a special focus is given to host-pathogen protein-protein interaction databases. Finally, we illustrate several phylogenetic and phylodynamic tools, combining information on algorithms and features with practical information on how to use them and case studies that validate their usefulness. Databases and tools for functional inference will be covered in the next article of this series: Bioinformatics goes viral: II. Sequence-based and structure-based functional analyses for boosting virus research.","PeriodicalId":501326,"journal":{"name":"Viruses","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142206898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aidan McGraw, Grace Hillmer, Stefania M. Medehincu, Yuta Hikichi, Sophia Gagliardi, Kedhar Narayan, Hasset Tibebe, Dacia Marquez, Lilia Mei Bose, Adleigh Keeting, Coco Izumi, Kevin Peese, Samit Joshi, Mark Krystal, Kathleen L. DeCicco-Skinner, Eric O. Freed, Luca Sardo, Taisuke Izumi
HIV-1 virion maturation is an essential step in the viral replication cycle to produce infectious virus particles. Gag and Gag-Pol polyproteins are assembled at the plasma membrane of the virus-producer cells and bud from it to the extracellular compartment. The newly released progeny virions are initially immature and noninfectious. However, once the Gag polyprotein is cleaved by the viral protease in progeny virions, the mature capsid proteins assemble to form the fullerene core. This core, harboring two copies of viral genomic RNA, transforms the virion morphology into infectious virus particles. This morphological transformation is referred to as maturation. Virion maturation influences the distribution of the Env glycoprotein on the virion surface and induces conformational changes necessary for the subsequent interaction with the CD4 receptor. Several host factors, including proteins like cyclophilin A, metabolites such as IP6, and lipid rafts containing sphingomyelins, have been demonstrated to have an influence on virion maturation. This review article delves into the processes of virus maturation and Env glycoprotein recruitment, with an emphasis on the role of host cell factors and environmental conditions. Additionally, we discuss microscopic technologies for assessing virion maturation and the development of current antivirals specifically targeting this critical step in viral replication, offering long-acting therapeutic options.
{"title":"Exploring HIV-1 Maturation: A New Frontier in Antiviral Development","authors":"Aidan McGraw, Grace Hillmer, Stefania M. Medehincu, Yuta Hikichi, Sophia Gagliardi, Kedhar Narayan, Hasset Tibebe, Dacia Marquez, Lilia Mei Bose, Adleigh Keeting, Coco Izumi, Kevin Peese, Samit Joshi, Mark Krystal, Kathleen L. DeCicco-Skinner, Eric O. Freed, Luca Sardo, Taisuke Izumi","doi":"10.3390/v16091423","DOIUrl":"https://doi.org/10.3390/v16091423","url":null,"abstract":"HIV-1 virion maturation is an essential step in the viral replication cycle to produce infectious virus particles. Gag and Gag-Pol polyproteins are assembled at the plasma membrane of the virus-producer cells and bud from it to the extracellular compartment. The newly released progeny virions are initially immature and noninfectious. However, once the Gag polyprotein is cleaved by the viral protease in progeny virions, the mature capsid proteins assemble to form the fullerene core. This core, harboring two copies of viral genomic RNA, transforms the virion morphology into infectious virus particles. This morphological transformation is referred to as maturation. Virion maturation influences the distribution of the Env glycoprotein on the virion surface and induces conformational changes necessary for the subsequent interaction with the CD4 receptor. Several host factors, including proteins like cyclophilin A, metabolites such as IP6, and lipid rafts containing sphingomyelins, have been demonstrated to have an influence on virion maturation. This review article delves into the processes of virus maturation and Env glycoprotein recruitment, with an emphasis on the role of host cell factors and environmental conditions. Additionally, we discuss microscopic technologies for assessing virion maturation and the development of current antivirals specifically targeting this critical step in viral replication, offering long-acting therapeutic options.","PeriodicalId":501326,"journal":{"name":"Viruses","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142206894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Muhammad Zubair Shabbir, Sahar Mahmood, Aziz Ul-Rahman, Ashley C. Banyard, Craig S. Ross
The virulent form of Avian paramyxovirus-1 (APMV-1), commonly known as Newcastle Disease Virus (NDV), is a pathogen with global implications for avian health, affecting both wild and domestic bird populations. In Pakistan, recurrent Newcastle Disease (caused by NDV) outbreaks have posed significant challenges to the poultry industry. Extensive surveillance in Pakistan over 20 years has demonstrated a dynamic genetic diversity among circulating APMV-1 strains, emphasizing the potential necessity for customized vaccination strategies and continuous surveillance. In this study, 13 APMV-1-positive isolates harboring four different APMV-1 genotypes circulating throughout Pakistan were identified. These included the highly virulent genotypes VII and XIII, genotype XXI, commonly associated with Columbiformes, and genotype II, hypothesized to have been detected following vaccination. These findings underscore the intricate interplay of mutational events and host-immune interactions shaping the evolving NDV landscape. This study advances our understanding of the evolutionary dynamics of APMV-1 in Pakistan, highlighting the need for tailored vaccination strategies and continuous surveillance to enable effective APMV-1 management in avian populations, further emphasizing the importance of globally coordinated strategies to tackle APMV-1, given its profound impact on wild and domestic birds.
{"title":"Genomic Diversity and Evolutionary Insights of Avian Paramyxovirus-1 in Avian Populations in Pakistan","authors":"Muhammad Zubair Shabbir, Sahar Mahmood, Aziz Ul-Rahman, Ashley C. Banyard, Craig S. Ross","doi":"10.3390/v16091414","DOIUrl":"https://doi.org/10.3390/v16091414","url":null,"abstract":"The virulent form of Avian paramyxovirus-1 (APMV-1), commonly known as Newcastle Disease Virus (NDV), is a pathogen with global implications for avian health, affecting both wild and domestic bird populations. In Pakistan, recurrent Newcastle Disease (caused by NDV) outbreaks have posed significant challenges to the poultry industry. Extensive surveillance in Pakistan over 20 years has demonstrated a dynamic genetic diversity among circulating APMV-1 strains, emphasizing the potential necessity for customized vaccination strategies and continuous surveillance. In this study, 13 APMV-1-positive isolates harboring four different APMV-1 genotypes circulating throughout Pakistan were identified. These included the highly virulent genotypes VII and XIII, genotype XXI, commonly associated with Columbiformes, and genotype II, hypothesized to have been detected following vaccination. These findings underscore the intricate interplay of mutational events and host-immune interactions shaping the evolving NDV landscape. This study advances our understanding of the evolutionary dynamics of APMV-1 in Pakistan, highlighting the need for tailored vaccination strategies and continuous surveillance to enable effective APMV-1 management in avian populations, further emphasizing the importance of globally coordinated strategies to tackle APMV-1, given its profound impact on wild and domestic birds.","PeriodicalId":501326,"journal":{"name":"Viruses","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142206919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hamidreza Karimi-Sari, Gregory M. Lucas, Katie Zook, Brian Weir, Miles Landry, Susan G. Sherman, Kathleen R. Page, Oluwaseun Falade-Nwulia
Background: Hepatitis C virus (HCV) infection and hazardous alcohol use are both preventable causes of morbidity and mortality among people who inject drugs (PWID). In the general population, hazardous alcohol is associated with a reduced likelihood of HCV treatment initiation. Less is known about the prevalence and impact of hazardous alcohol use on direct-acting antiviral (DAA) therapy initiation among PWID with active injection drug use. Methods: PWID were recruited via street outreach in Baltimore, Maryland, between 2018 and 2019 and were enrolled in a study cohort. Participants completed a study survey and underwent HCV testing. Self-reported DAA therapy initiation was evaluated at follow-up visits every six months. Hazardous alcohol use was determined based on an AUDIT-C score of ≥4 for men or ≥3 for women. Data were analyzed using multivariable logistic regression with generalized estimating equations. Results: Of the 720 PWID recruited, 291 had detectable HCV RNA, and only 134 were aware of their HCV infection. The mean (±standard deviation) age of those that were aware of their infection was 48.7 (±10.3) years, with a slight majority (53.0%) being male and predominantly African American (64.9%). The majority (80/134, 59.7%) met criteria for hazardous alcohol use. Only 16 (11.9%) PWID reported DAA therapy initiation within six months, and 20 (14.9%) reported it within 12 months of follow-up. Hazardous alcohol use (aOR = 1.23, 95% CI = 0.43–3.53) was not associated with DAA treatment initiation. Conclusions: There was a high prevalence of hazardous alcohol use, low rates of oral DAA therapy initiation, and no association between self-reported hazardous alcohol use and initiation of oral DAA therapy in our sample of PWID that were aware of their chronic HCV infection. Strategies to increase HCV treatment uptake in PWID with active drug use are urgently needed and should integrate alcohol and drug use evaluation and care.
{"title":"Hazardous Alcohol Use and Its Effect on Direct-Acting Antiviral Therapy Initiation among People with Active Injection Drug Use and Current Hepatitis C Infection","authors":"Hamidreza Karimi-Sari, Gregory M. Lucas, Katie Zook, Brian Weir, Miles Landry, Susan G. Sherman, Kathleen R. Page, Oluwaseun Falade-Nwulia","doi":"10.3390/v16091416","DOIUrl":"https://doi.org/10.3390/v16091416","url":null,"abstract":"Background: Hepatitis C virus (HCV) infection and hazardous alcohol use are both preventable causes of morbidity and mortality among people who inject drugs (PWID). In the general population, hazardous alcohol is associated with a reduced likelihood of HCV treatment initiation. Less is known about the prevalence and impact of hazardous alcohol use on direct-acting antiviral (DAA) therapy initiation among PWID with active injection drug use. Methods: PWID were recruited via street outreach in Baltimore, Maryland, between 2018 and 2019 and were enrolled in a study cohort. Participants completed a study survey and underwent HCV testing. Self-reported DAA therapy initiation was evaluated at follow-up visits every six months. Hazardous alcohol use was determined based on an AUDIT-C score of ≥4 for men or ≥3 for women. Data were analyzed using multivariable logistic regression with generalized estimating equations. Results: Of the 720 PWID recruited, 291 had detectable HCV RNA, and only 134 were aware of their HCV infection. The mean (±standard deviation) age of those that were aware of their infection was 48.7 (±10.3) years, with a slight majority (53.0%) being male and predominantly African American (64.9%). The majority (80/134, 59.7%) met criteria for hazardous alcohol use. Only 16 (11.9%) PWID reported DAA therapy initiation within six months, and 20 (14.9%) reported it within 12 months of follow-up. Hazardous alcohol use (aOR = 1.23, 95% CI = 0.43–3.53) was not associated with DAA treatment initiation. Conclusions: There was a high prevalence of hazardous alcohol use, low rates of oral DAA therapy initiation, and no association between self-reported hazardous alcohol use and initiation of oral DAA therapy in our sample of PWID that were aware of their chronic HCV infection. Strategies to increase HCV treatment uptake in PWID with active drug use are urgently needed and should integrate alcohol and drug use evaluation and care.","PeriodicalId":501326,"journal":{"name":"Viruses","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142206899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Begomoviruses, transmitted by the whitefly Bemisia tabaci, pose significant threats to global agriculture due to their severe impact on various crops. Among the satellite molecules associated with begomoviruses, betasatellites play a crucial role in enhancing disease severity and yield losses. The spread and association of these molecules with helper viruses in host plants are thus matters of concern. Here, we focus on the propagation of betasatellites and, more specifically, on their transfer between different helper viruses and hosts through vector transmission. Our results show that the cotton leaf curl Gezira betasatellite (CLCuGeB), initially acquired with its helper virus cotton leaf curl Gezira virus (CLCuGeV) from an okra plant, can be transmitted and assisted by a different helper virus, tomato yellow leaf curl virus (TYLCV), in a different host plant (tomato plant). The new association can be formed whether TYLCV and CLCuGeB encounter each other in a host plant previously infected with TYLCV or in whiteflies having acquired the different components separately. Our findings reveal two pathways by which betasatellites can be transferred between helper viruses and host plants and highlight the ability of betasatellites to spread in begomovirus-infected environments.
{"title":"Demonstration of Insect Vector-Mediated Transfer of a Betasatellite between Two Helper Viruses","authors":"Noun Fouad, Martine Granier, Stéphane Blanc, Gaël Thébaud, Cica Urbino","doi":"10.3390/v16091420","DOIUrl":"https://doi.org/10.3390/v16091420","url":null,"abstract":"Begomoviruses, transmitted by the whitefly Bemisia tabaci, pose significant threats to global agriculture due to their severe impact on various crops. Among the satellite molecules associated with begomoviruses, betasatellites play a crucial role in enhancing disease severity and yield losses. The spread and association of these molecules with helper viruses in host plants are thus matters of concern. Here, we focus on the propagation of betasatellites and, more specifically, on their transfer between different helper viruses and hosts through vector transmission. Our results show that the cotton leaf curl Gezira betasatellite (CLCuGeB), initially acquired with its helper virus cotton leaf curl Gezira virus (CLCuGeV) from an okra plant, can be transmitted and assisted by a different helper virus, tomato yellow leaf curl virus (TYLCV), in a different host plant (tomato plant). The new association can be formed whether TYLCV and CLCuGeB encounter each other in a host plant previously infected with TYLCV or in whiteflies having acquired the different components separately. Our findings reveal two pathways by which betasatellites can be transferred between helper viruses and host plants and highlight the ability of betasatellites to spread in begomovirus-infected environments.","PeriodicalId":501326,"journal":{"name":"Viruses","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142206920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Odelia Orbaum-Harel, Anna Sloutskin, Inna Kalt, Ronit Sarid
Kaposi’s sarcoma-associated herpesvirus (KSHV) is a cancer-causing virus that establishes life-long infection. KSHV is implicated in the etiology of Kaposi’s sarcoma, and a number of rare hematopoietic malignancies. The present study focuses on the KSHV open reading frame 20 (ORF20), a member of the conserved herpesvirus UL24 protein family containing five conserved homology domains and a conserved PD-(D/E)XK putative endonuclease motif, whose nuclease function has not been established to date. ORF20 encodes three co-linear protein isoforms, full length, intermediate, and short, though their differential functions are unknown. In an effort to determine the role of ORF20 during KSHV infection, we generated a recombinant ORF20-Null KSHV genome, which fails to express all three ORF20 isoforms. This genome was reconstituted in iSLK cells to establish a latent infection, which resulted in an accelerated transcription of viral mRNAs, an earlier accumulation of viral lytic proteins, an increase in the quantity of viral DNA copies, and a significant decrease in viral yield upon lytic reactivation. This was accompanied by early cell death of cells infected with the ORF20-Null virus. Functional complementation of the ORF20-Null mutant with the short ORF20 isoform rescued KSHV production, whereas its endonuclease mutant form failed to enhance lytic reactivation. Complementation with the short isoform further revealed a decrease in cell death as compared with ORF20-Null virus. Finally, expression of IL6 and CXCL8, previously shown to be affected by the hCMV UL24 homolog, was relatively low upon reactivation of cells infected with the ORF20-Null virus. These findings suggest that ORF20 protein, with its putative endonuclease motif, promotes coordinated lytic reactivation for increased infectious particle production.
{"title":"KSHV ORF20 Promotes Coordinated Lytic Reactivation for Increased Infectious Particle Production","authors":"Odelia Orbaum-Harel, Anna Sloutskin, Inna Kalt, Ronit Sarid","doi":"10.3390/v16091418","DOIUrl":"https://doi.org/10.3390/v16091418","url":null,"abstract":"Kaposi’s sarcoma-associated herpesvirus (KSHV) is a cancer-causing virus that establishes life-long infection. KSHV is implicated in the etiology of Kaposi’s sarcoma, and a number of rare hematopoietic malignancies. The present study focuses on the KSHV open reading frame 20 (ORF20), a member of the conserved herpesvirus UL24 protein family containing five conserved homology domains and a conserved PD-(D/E)XK putative endonuclease motif, whose nuclease function has not been established to date. ORF20 encodes three co-linear protein isoforms, full length, intermediate, and short, though their differential functions are unknown. In an effort to determine the role of ORF20 during KSHV infection, we generated a recombinant ORF20-Null KSHV genome, which fails to express all three ORF20 isoforms. This genome was reconstituted in iSLK cells to establish a latent infection, which resulted in an accelerated transcription of viral mRNAs, an earlier accumulation of viral lytic proteins, an increase in the quantity of viral DNA copies, and a significant decrease in viral yield upon lytic reactivation. This was accompanied by early cell death of cells infected with the ORF20-Null virus. Functional complementation of the ORF20-Null mutant with the short ORF20 isoform rescued KSHV production, whereas its endonuclease mutant form failed to enhance lytic reactivation. Complementation with the short isoform further revealed a decrease in cell death as compared with ORF20-Null virus. Finally, expression of IL6 and CXCL8, previously shown to be affected by the hCMV UL24 homolog, was relatively low upon reactivation of cells infected with the ORF20-Null virus. These findings suggest that ORF20 protein, with its putative endonuclease motif, promotes coordinated lytic reactivation for increased infectious particle production.","PeriodicalId":501326,"journal":{"name":"Viruses","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142206924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Vincent N. Azzolino, Ala M. Shaqra, Akbar Ali, Nese Kurt Yilmaz, Celia A. Schiffer
Enterovirus-D68 (EV68) has emerged as a global health concern over the last decade with severe symptomatic infections resulting in long-lasting neurological deficits and death. Unfortunately, there are currently no FDA-approved antiviral drugs for EV68 or any other non-polio enterovirus. One particularly attractive class of potential drugs are small molecules inhibitors, which can target the conserved active site of EV68-3C protease. For other viral proteases, we have demonstrated that the emergence of drug resistance can be minimized by designing inhibitors that leverage the evolutionary constraints of substrate specificity. However, the structural characterization of EV68-3C protease bound to its substrates has been lacking. Here, we have determined the substrate specificity of EV68-3C protease through molecular modeling, molecular dynamics (MD) simulations, and co-crystal structures. Molecular models enabled us to successfully characterize the conserved hydrogen-bond networks between EV68-3C protease and the peptides corresponding to the viral cleavage sites. In addition, co-crystal structures we determined have revealed substrate-induced conformational changes of the protease which involved new interactions, primarily surrounding the S1 pocket. We calculated the substrate envelope, the three-dimensional consensus volume occupied by the substrates within the active site. With the elucidation of the EV68-3C protease substrate envelope, we evaluated how 3C protease inhibitors, AG7088 and SG-85, fit within the active site to predict potential resistance mutations.
{"title":"Elucidating the Substrate Envelope of Enterovirus 68-3C Protease: Structural Basis of Specificity and Potential Resistance","authors":"Vincent N. Azzolino, Ala M. Shaqra, Akbar Ali, Nese Kurt Yilmaz, Celia A. Schiffer","doi":"10.3390/v16091419","DOIUrl":"https://doi.org/10.3390/v16091419","url":null,"abstract":"Enterovirus-D68 (EV68) has emerged as a global health concern over the last decade with severe symptomatic infections resulting in long-lasting neurological deficits and death. Unfortunately, there are currently no FDA-approved antiviral drugs for EV68 or any other non-polio enterovirus. One particularly attractive class of potential drugs are small molecules inhibitors, which can target the conserved active site of EV68-3C protease. For other viral proteases, we have demonstrated that the emergence of drug resistance can be minimized by designing inhibitors that leverage the evolutionary constraints of substrate specificity. However, the structural characterization of EV68-3C protease bound to its substrates has been lacking. Here, we have determined the substrate specificity of EV68-3C protease through molecular modeling, molecular dynamics (MD) simulations, and co-crystal structures. Molecular models enabled us to successfully characterize the conserved hydrogen-bond networks between EV68-3C protease and the peptides corresponding to the viral cleavage sites. In addition, co-crystal structures we determined have revealed substrate-induced conformational changes of the protease which involved new interactions, primarily surrounding the S1 pocket. We calculated the substrate envelope, the three-dimensional consensus volume occupied by the substrates within the active site. With the elucidation of the EV68-3C protease substrate envelope, we evaluated how 3C protease inhibitors, AG7088 and SG-85, fit within the active site to predict potential resistance mutations.","PeriodicalId":501326,"journal":{"name":"Viruses","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142206932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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