Pub Date : 2024-10-15DOI: 10.1016/j.antiviral.2024.106021
Marta Butrym , Fabian Byvald , Marfa Blanter , Emma E. Ringqvist , Svitlana Vasylovska , Varpu Marjomäki , Joey Lau , Virginia M. Stone , Malin Flodström-Tullberg
Enteroviruses, which infect via the gut, have been implicated in type 1 diabetes (T1D) development. Prolonged faecal shedding of enterovirus has been associated with islet autoimmunity. Additionally, enteroviral proteins and viral RNA have been detected in the pancreatic islets of individuals with recent-onset T1D, implicating their possible role in beta cell destruction. Despite this, no approved antiviral drugs currently exist that specifically target enterovirus infections for utilisation in disease interventions.
Drug repurposing allows for the discovery of new clinical uses for existing drugs and can expedite drug discovery. Previously, the cancer drug Vemurafenib demonstrated unprecedented antiviral activity against several enteroviruses. In the present study, we assessed the efficacy of Vemurafenib and an analogue thereof in preventing infection or reducing the replication of enteroviruses associated with T1D. We tested Vemurafenib in intestinal epithelial cells (IECs) and insulin-producing beta cells. Additionally, we established a protocol for infecting human stem cell-derived islets (SC-islets) and used Vemurafenib and its analogue in this model.
Our studies revealed that Vemurafenib exhibited strong antiviral properties in IECs and a beta cell line. The antiviral effect was also seen with the Vemurafenib analogue. SC-islets expressed the viral receptors CAR and DAF, with their highest expression in insulin- and glucagon-positive cells, respectively. SC-islets were successfully infected by CVBs and the antiviral activity of Vemurafenib and its analogue was confirmed in most SC-islet batches.
In summary, our observations suggest that Vemurafenib and its analogue warrant further exploration as potential antiviral agents for the treatment of enterovirus-induced diseases, including T1D.
{"title":"Vemurafenib inhibits the replication of diabetogenic enteroviruses in intestinal epithelial and pancreatic beta cells","authors":"Marta Butrym , Fabian Byvald , Marfa Blanter , Emma E. Ringqvist , Svitlana Vasylovska , Varpu Marjomäki , Joey Lau , Virginia M. Stone , Malin Flodström-Tullberg","doi":"10.1016/j.antiviral.2024.106021","DOIUrl":"10.1016/j.antiviral.2024.106021","url":null,"abstract":"<div><div>Enteroviruses, which infect via the gut, have been implicated in type 1 diabetes (T1D) development. Prolonged faecal shedding of enterovirus has been associated with islet autoimmunity. Additionally, enteroviral proteins and viral RNA have been detected in the pancreatic islets of individuals with recent-onset T1D, implicating their possible role in beta cell destruction. Despite this, no approved antiviral drugs currently exist that specifically target enterovirus infections for utilisation in disease interventions.</div><div>Drug repurposing allows for the discovery of new clinical uses for existing drugs and can expedite drug discovery. Previously, the cancer drug Vemurafenib demonstrated unprecedented antiviral activity against several enteroviruses. In the present study, we assessed the efficacy of Vemurafenib and an analogue thereof in preventing infection or reducing the replication of enteroviruses associated with T1D. We tested Vemurafenib in intestinal epithelial cells (IECs) and insulin-producing beta cells. Additionally, we established a protocol for infecting human stem cell-derived islets (SC-islets) and used Vemurafenib and its analogue in this model.</div><div>Our studies revealed that Vemurafenib exhibited strong antiviral properties in IECs and a beta cell line. The antiviral effect was also seen with the Vemurafenib analogue. SC-islets expressed the viral receptors CAR and DAF, with their highest expression in insulin- and glucagon-positive cells, respectively. SC-islets were successfully infected by CVBs and the antiviral activity of Vemurafenib and its analogue was confirmed in most SC-islet batches.</div><div>In summary, our observations suggest that Vemurafenib and its analogue warrant further exploration as potential antiviral agents for the treatment of enterovirus-induced diseases, including T1D.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"231 ","pages":"Article 106021"},"PeriodicalIF":4.5,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-15DOI: 10.1016/j.antiviral.2024.106020
Patricia García-Martínez , Laura Gisbert-Ferrándiz , Ángeles Álvarez , Juan V. Esplugues , Ana Blas-García
Growing evidence associates antiretroviral therapies containing integrase strand transfer inhibitors or tenofovir alafenamide (TAF) with increased weight gain and metabolic diseases, but the underlying mechanisms remain unclear. This study evaluated the impact of lamivudine, dolutegravir (DTG), bictegravir (BIC), tenofovir disoproxil fumarate, and TAF on metabolic alterations, and explored glucose homeostasis and mitochondrial stress as potential mechanisms. These pathways were analyzed both in vivo (C57BL/6J mice treated with the abovementioned drugs or vehicle for 16 weeks) and in vitro (in Hep3B cells). Mice treated with BIC exhibited higher glucose levels and a slower decrease during a glucose tolerance test. Functional enrichment analyses of livers from antiretroviral-treated mice revealed that only BIC altered the cellular response to insulin and induced a gluconeogenic-favoring profile, with Fgf21 playing a significant role. In vitro, BIC significantly reduced hepatocyte glucose uptake in a concentration-dependent manner, both under basal conditions and post-insulin stimulation, while the other drugs produced no significant changes. Hep3B cells treated with clinically relevant concentrations of BIC exhibited significant alterations in the mRNA expression of enzymes related to glucose metabolism. Both DTG and BIC reduced mitochondrial dehydrogenase activity, but only BIC increased reactive oxygen species, mitochondrial membrane potential, and cellular granularity, thereby indicating mitochondrial stress. BIC promoted mitochondrial dysfunction, modified carbohydrate metabolism and glucose consumption in hepatocytes, and altered glucose tolerance and gluconeogenesis regulation in mice. These findings suggest that BIC contributes to insulin resistance and diabetes in people living with HIV, warranting clinical studies to clarify its association with carbohydrate metabolism disorders.
{"title":"Bictegravir alters glucose tolerance in vivo and causes hepatic mitochondrial dysfunction","authors":"Patricia García-Martínez , Laura Gisbert-Ferrándiz , Ángeles Álvarez , Juan V. Esplugues , Ana Blas-García","doi":"10.1016/j.antiviral.2024.106020","DOIUrl":"10.1016/j.antiviral.2024.106020","url":null,"abstract":"<div><div>Growing evidence associates antiretroviral therapies containing integrase strand transfer inhibitors or tenofovir alafenamide (TAF) with increased weight gain and metabolic diseases, but the underlying mechanisms remain unclear. This study evaluated the impact of lamivudine, dolutegravir (DTG), bictegravir (BIC), tenofovir disoproxil fumarate, and TAF on metabolic alterations, and explored glucose homeostasis and mitochondrial stress as potential mechanisms. These pathways were analyzed both <em>in vivo</em> (C57BL/6J mice treated with the abovementioned drugs or vehicle for 16 weeks) and <em>in vitro</em> (in Hep3B cells). Mice treated with BIC exhibited higher glucose levels and a slower decrease during a glucose tolerance test. Functional enrichment analyses of livers from antiretroviral-treated mice revealed that only BIC altered the cellular response to insulin and induced a gluconeogenic-favoring profile, with <em>Fgf21</em> playing a significant role. <em>In vitro</em>, BIC significantly reduced hepatocyte glucose uptake in a concentration-dependent manner, both under basal conditions and post-insulin stimulation, while the other drugs produced no significant changes. Hep3B cells treated with clinically relevant concentrations of BIC exhibited significant alterations in the mRNA expression of enzymes related to glucose metabolism. Both DTG and BIC reduced mitochondrial dehydrogenase activity, but only BIC increased reactive oxygen species, mitochondrial membrane potential, and cellular granularity, thereby indicating mitochondrial stress. BIC promoted mitochondrial dysfunction, modified carbohydrate metabolism and glucose consumption in hepatocytes, and altered glucose tolerance and gluconeogenesis regulation in mice. These findings suggest that BIC contributes to insulin resistance and diabetes in people living with HIV, warranting clinical studies to clarify its association with carbohydrate metabolism disorders.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"231 ","pages":"Article 106020"},"PeriodicalIF":4.5,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-11DOI: 10.1016/j.antiviral.2024.106017
Yijie Tang , Mingzhu Xu , Cong Wang , Min Wu , Lyuyin Hu , Jin Li , Wei Lu , Ye Zheng , Min Zhang , Xizi Jiang , Chuanwu Zhu , Jennifer Audsley , Pisit Tangkijvanich , Anchalee Avihingsanon , Shu Song , Shuangzhe Liu , Sharon R. Lewin , Jacob George , Mark W. Douglas , Yun Ling , Xiaonan Zhang
Chronic infection with Hepatitis B Virus (HBV) often results in a dysfunctional virus-specific T cell response hampering viral clearance. Paradoxically, intrahepatic inflammatory responses that contribute more to liver histopathology than to viral suppression are commonly observed, which are widely believed to be cell mediated. The involvement of humoral immunity in this process however is not well documented. To investigate the possible roles of HBV Capsid-Antibody Complexes (CACs) in eliciting chronic liver inflammation, we developed a novel microplate-based assay for the quantification of CACs in serum. The CACs assay showed high sensitivity and specificity with its readout closely correlating with the molecular features of CACs. A cross-sectional study on untreated chronic hepatitis B (CHB) patients showed a 77% positive rate for CACs with significant association with alanine transaminase (ALT), intrahepatic inflammation, and complement deposition, suggestive of its functional role in hepatic injury. Multiple staining of complement activation fragment C4d with major leukocyte and myofibroblast markers revealed an intertwined picture in periportal area with a morphology reminiscent of “piecemeal necrosis”. In a pooled cohort with ALT levels lower than 40 IU/ml, CACs alone revealed subclinical liver inflammation. We provide definitive evidence for a causative role for CACs in complement-mediated intrahepatic immunopathology, an additional mechanism contributing to liver damage in CHB. Assessment of CACs in serum complements current clinical markers for assessing CHB associated inflammation.
{"title":"Circulating capsid-antibody-complexes (CACs) drive intrahepatic complement deposition and inform subclinical liver inflammation in chronic hepatitis B","authors":"Yijie Tang , Mingzhu Xu , Cong Wang , Min Wu , Lyuyin Hu , Jin Li , Wei Lu , Ye Zheng , Min Zhang , Xizi Jiang , Chuanwu Zhu , Jennifer Audsley , Pisit Tangkijvanich , Anchalee Avihingsanon , Shu Song , Shuangzhe Liu , Sharon R. Lewin , Jacob George , Mark W. Douglas , Yun Ling , Xiaonan Zhang","doi":"10.1016/j.antiviral.2024.106017","DOIUrl":"10.1016/j.antiviral.2024.106017","url":null,"abstract":"<div><div>Chronic infection with Hepatitis B Virus (HBV) often results in a dysfunctional virus-specific T cell response hampering viral clearance. Paradoxically, intrahepatic inflammatory responses that contribute more to liver histopathology than to viral suppression are commonly observed, which are widely believed to be cell mediated. The involvement of humoral immunity in this process however is not well documented. To investigate the possible roles of HBV Capsid-Antibody Complexes (CACs) in eliciting chronic liver inflammation, we developed a novel microplate-based assay for the quantification of CACs in serum. The CACs assay showed high sensitivity and specificity with its readout closely correlating with the molecular features of CACs. A cross-sectional study on untreated chronic hepatitis B (CHB) patients showed a 77% positive rate for CACs with significant association with alanine transaminase (ALT), intrahepatic inflammation, and complement deposition, suggestive of its functional role in hepatic injury. Multiple staining of complement activation fragment C4d with major leukocyte and myofibroblast markers revealed an intertwined picture in periportal area with a morphology reminiscent of “piecemeal necrosis”. In a pooled cohort with ALT levels lower than 40 IU/ml, CACs alone revealed subclinical liver inflammation. We provide definitive evidence for a causative role for CACs in complement-mediated intrahepatic immunopathology, an additional mechanism contributing to liver damage in CHB. Assessment of CACs in serum complements current clinical markers for assessing CHB associated inflammation.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"231 ","pages":"Article 106017"},"PeriodicalIF":4.5,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142432764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-10DOI: 10.1016/j.antiviral.2024.106019
Junwei Zhou , Peng Sun , Yuanqing Wang , Yuting Shi , Chaoqun Chen , Wenwen Xiao , Runhui Qiu , Ting Cheng , Liurong Fang , Shaobo Xiao
Porcine deltacoronavirus (PDCoV) is an emerging swine enteric coronavirus with zoonotic potential. PDCoV spillovers were recently detected in Haitian children with acute undifferentiated febrile illness, underscoring the urgent need to develop anti-PDCoV therapeutics. Coronavirus 3C-like protease (CoV 3CLpro) is essential for viral replication, and therefore provides an attractive target for drugs directed against CoV. Here, we initially evaluated the anti-PDCoV effect of Nirmatrelvir (PF-07321332), an FDA-approved anti-SARS-CoV-2 drug targeting viral 3CLpro. Regrettably, a very limited anti-PDCoV effect was achieved. By analyzing the binding modes of Nirmatrelvir with PDCoV 3CLpro and SARS-CoV-2 3CLpro, we demonstrated that the S2 pocket of 3CLpro is the primary factor underlying the differential inhibitory potency of Nirmatrelvir against different CoV 3CLpros. Based on the specific characteristics of the S2 pocket of PDCoV 3CLpro, four derivatives of Nirmatrelvir (compounds T1–T4) with substituted P2 moieties were synthesized. Compound T1, with an isobutyl at the P2 site, displayed improved anti-PDCoV activity invitro (cell infection model) and invivo (embryonated chicken egg infection model), and therefore is a potential candidate drug to combat PDCoV. Together, our results identify the substrate-binding mode and substrate specificity of PDCoV 3CLpro, providing insight into the optimization of Nirmatrelvir as an antiviral therapeutic agent against PDCoV.
{"title":"Design and biological evaluation of candidate drugs against zoonotic porcine deltacoronavirus (PDCoV)","authors":"Junwei Zhou , Peng Sun , Yuanqing Wang , Yuting Shi , Chaoqun Chen , Wenwen Xiao , Runhui Qiu , Ting Cheng , Liurong Fang , Shaobo Xiao","doi":"10.1016/j.antiviral.2024.106019","DOIUrl":"10.1016/j.antiviral.2024.106019","url":null,"abstract":"<div><div>Porcine deltacoronavirus (PDCoV) is an emerging swine enteric coronavirus with zoonotic potential. PDCoV spillovers were recently detected in Haitian children with acute undifferentiated febrile illness, underscoring the urgent need to develop anti-PDCoV therapeutics. Coronavirus 3C-like protease (CoV 3CL<sup>pro</sup>) is essential for viral replication, and therefore provides an attractive target for drugs directed against CoV. Here, we initially evaluated the anti-PDCoV effect of Nirmatrelvir (PF-07321332), an FDA-approved anti-SARS-CoV-2 drug targeting viral 3CL<sup>pro</sup>. Regrettably, a very limited anti-PDCoV effect was achieved. By analyzing the binding modes of Nirmatrelvir with PDCoV 3CL<sup>pro</sup> and SARS-CoV-2 3CL<sup>pro</sup>, we demonstrated that the S2 pocket of 3CL<sup>pro</sup> is the primary factor underlying the differential inhibitory potency of Nirmatrelvir against different CoV 3CL<sup>pro</sup>s. Based on the specific characteristics of the S2 pocket of PDCoV 3CL<sup>pro</sup>, four derivatives of Nirmatrelvir (compounds T1–T4) with substituted P2 moieties were synthesized. Compound T1, with an isobutyl at the P2 site, displayed improved anti-PDCoV activity <em>in</em> <em>vitro</em> (cell infection model) and <em>in</em> <em>vivo</em> (embryonated chicken egg infection model), and therefore is a potential candidate drug to combat PDCoV. Together, our results identify the substrate-binding mode and substrate specificity of PDCoV 3CL<sup>pro</sup>, providing insight into the optimization of Nirmatrelvir as an antiviral therapeutic agent against PDCoV.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"231 ","pages":"Article 106019"},"PeriodicalIF":4.5,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142432763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-09DOI: 10.1016/j.antiviral.2024.106018
Younghoon Lee , Minjun Seo , Suk-hyun Yun , Minyeong Yu , Hyo Jin Kim , Hye Won Cho , Hee Won Byeon , Seong Ok Park , Erdenebileg Uyangaa , Hyunjin Jeon , Minhyeong Lee , Young Do Kwon , Seong Kug Eo
Lethal Dengue Hemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS) caused by Dengue virus (DENV) infection necessitate the development of effective treatments. Peptides derived from the N-terminal amphipathic α-helix of hepatitis C virus (HCV) NS5A exhibit antiviral activity by disrupting liposomes with high curvatures, such as virus envelopes. This study engineered five peptides from HCV genotype 3a NS5A N-terminal α-helix and screened them for neutralizing efficacy against three DENV serotypes. Two peptides, 3a 3/20 and DS-05, showed superior therapeutic efficacy against DENV and were further evaluated in treating DHF/DSS induced by mouse-adapted DENV infection. Administration of 3a 3/20 and DS-05 post-infection significantly improved mortality and weight loss associated with DHF/DSS in AG6 mice. These peptides reduced viral load in internal organs and viremia to levels comparable with the positive control drug, JNJ-A07, a DENV NS3-NS4B inhibitor. Additionally, they attenuated the cytokine storm in the blood and expression of inflammatory cytokines in internal organ tissues, ameliorating liver and kidney dysfunction after DENV infection. Histopathological analysis revealed significant suppression of damages in internal organs. These findings suggest that the 3a 3/20 and DS-05 peptides improve clinical symptoms of DHF/DSS induced by DENV infection, indicating their potential for clinical application.
登革病毒（DENV）感染引起的致命性登革出血热（DHF）和登革休克综合征（DSS）需要开发有效的治疗方法。从丙型肝炎病毒（HCV）NS5A 的 N 端两亲α-螺旋中提取的肽具有抗病毒活性，能破坏病毒包膜等具有高弯曲度的脂质体。本研究从 HCV 基因型 3a NS5A N 端 α-helix 中设计了五种多肽，并筛选了它们对三种 DENV 血清型的中和效力。3a 3/20和DS-05这两种肽对DENV表现出卓越的疗效，并在治疗小鼠适应DENV感染诱发的DHF/DSS方面进行了进一步评估。感染后服用3a 3/20和DS-05可明显改善AG6小鼠因DHF/DSS引起的死亡率和体重下降。这些肽能降低内脏器官中的病毒载量和病毒血症，其水平与阳性对照药物JNJ-A07（一种DENV NS3-NS4B抑制剂）相当。此外，它们还能减轻血液中的细胞因子风暴和内脏组织中炎症细胞因子的表达，改善 DENV 感染后的肝肾功能障碍。组织病理学分析表明，内脏器官的损伤明显减轻。这些研究结果表明，3a 3/20和DS-05肽能改善由DENV感染引起的DHF/DSS临床症状，表明它们具有临床应用潜力。
{"title":"Inhibitory peptides derived from Hepatitis C virus NS5A for reducing clinical symptoms of dengue virus infection","authors":"Younghoon Lee , Minjun Seo , Suk-hyun Yun , Minyeong Yu , Hyo Jin Kim , Hye Won Cho , Hee Won Byeon , Seong Ok Park , Erdenebileg Uyangaa , Hyunjin Jeon , Minhyeong Lee , Young Do Kwon , Seong Kug Eo","doi":"10.1016/j.antiviral.2024.106018","DOIUrl":"10.1016/j.antiviral.2024.106018","url":null,"abstract":"<div><div>Lethal Dengue Hemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS) caused by Dengue virus (DENV) infection necessitate the development of effective treatments. Peptides derived from the N-terminal amphipathic α-helix of hepatitis C virus (HCV) NS5A exhibit antiviral activity by disrupting liposomes with high curvatures, such as virus envelopes. This study engineered five peptides from HCV genotype 3a NS5A N-terminal α-helix and screened them for neutralizing efficacy against three DENV serotypes. Two peptides, 3a 3/20 and DS-05, showed superior therapeutic efficacy against DENV and were further evaluated in treating DHF/DSS induced by mouse-adapted DENV infection. Administration of 3a 3/20 and DS-05 post-infection significantly improved mortality and weight loss associated with DHF/DSS in AG6 mice. These peptides reduced viral load in internal organs and viremia to levels comparable with the positive control drug, JNJ-A07, a DENV NS3-NS4B inhibitor. Additionally, they attenuated the cytokine storm in the blood and expression of inflammatory cytokines in internal organ tissues, ameliorating liver and kidney dysfunction after DENV infection. Histopathological analysis revealed significant suppression of damages in internal organs. These findings suggest that the 3a 3/20 and DS-05 peptides improve clinical symptoms of DHF/DSS induced by DENV infection, indicating their potential for clinical application.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"231 ","pages":"Article 106018"},"PeriodicalIF":4.5,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-28DOI: 10.1016/j.antiviral.2024.106016
Valentin Tilloy , Daniel Díaz-González , Lisa Laplace , Emilien Bisserier , Sunwen Chou , William D. Rawlinson , Guy Boivin , Fausto Baldanti , Tiziana Lazzarotto , Graciela Andrei , Hans H. Hirsch , María Ángeles Marcos , Detlef Michel , Sébastien Hantz , Sophie Alain
A comprehensive and accessible Herpesvirus drug resistance database was designed to serve as an international reference for diagnosis and clinical studies. This database available at https://www.unilim.fr/cnr-herpesvirus/outils/codexmv/includes both resistance-related mutations and natural polymorphisms. Initially designed for human cytomegalovirus, it will be expanded to include herpes simplex and varicella-zoster viruses. Newly published mutations and new mutations reported by users or collaborating expert laboratories will be reviewed by an international committee of reference laboratories before inclusion in the database. Coupled with the Herpesvirus Sequence Analysis tool (HSA) mutation reports from NGS or Sanger sequences, it will be an open source for researchers in the field of Herpesviruses. We hope to fill this unmet need for the development and standardization of resistance genotyping.
{"title":"Comprehensive Herpesviruses Antiviral drug Resistance Mutation Database (CHARMD)","authors":"Valentin Tilloy , Daniel Díaz-González , Lisa Laplace , Emilien Bisserier , Sunwen Chou , William D. Rawlinson , Guy Boivin , Fausto Baldanti , Tiziana Lazzarotto , Graciela Andrei , Hans H. Hirsch , María Ángeles Marcos , Detlef Michel , Sébastien Hantz , Sophie Alain","doi":"10.1016/j.antiviral.2024.106016","DOIUrl":"10.1016/j.antiviral.2024.106016","url":null,"abstract":"<div><div>A comprehensive and accessible Herpesvirus drug resistance database was designed to serve as an international reference for diagnosis and clinical studies. This database available at <span><span>https://www.unilim.fr/cnr-herpesvirus/outils/codexmv/</span><svg><path></path></svg></span>includes both resistance-related mutations and natural polymorphisms. Initially designed for human cytomegalovirus, it will be expanded to include herpes simplex and varicella-zoster viruses. Newly published mutations and new mutations reported by users or collaborating expert laboratories will be reviewed by an international committee of reference laboratories before inclusion in the database. Coupled with the Herpesvirus Sequence Analysis tool (HSA) mutation reports from NGS or Sanger sequences, it will be an open source for researchers in the field of Herpesviruses. We hope to fill this unmet need for the development and standardization of resistance genotyping.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"231 ","pages":"Article 106016"},"PeriodicalIF":4.5,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142340059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-27DOI: 10.1016/j.antiviral.2024.106015
Angela I. Schriek , David Falck , Manfred Wuhrer , Neeltje A. Kootstra , Marit J. van Gils , Steven W. de Taeye
Substantial reduction of the intact proviral reservoir is essential towards HIV-1 cure. In vivo administration of broadly neutralizing antibodies (bNAbs) targeting the HIV-1 envelope glycoprotein (Env) trimer can decrease the viral reservoir, through Fc-mediated killing of infected cells. In this study, we compared three commonly used antibody engineering strategies to enhance Fc-mediated effector functions: (i) glyco-engineering, (ii) protein engineering, and (iii) subclass/hinge modifications in a panel of anti-HIV-1 antibodies. We found that antibody-dependent cellular phagocytosis (ADCP) was improved by elongating the hinge domain and switching to an IgG3 constant domain. In addition, potent NK cell activation and ADCC activity was observed for afucosylated antibodies and antibodies bearing the GASDALIE mutations. The combination of these engineering strategies further increased NK cell activation and induced antibody dependent cytotoxicity (ADCC) of infected cells at low antibody concentrations. The bNAb N6 was most effective at killing HIV-1 infected cells, likely due to its high affinity and optimal angle of approach. Overall, the findings of this study are applicable to other antibody formats, and can aid the development of effective immunotherapies and antibody-based treatments for HIV-1 cure strategies.
{"title":"Functional comparison of Fc-engineering strategies to improve anti-HIV-1 antibody effector functions","authors":"Angela I. Schriek , David Falck , Manfred Wuhrer , Neeltje A. Kootstra , Marit J. van Gils , Steven W. de Taeye","doi":"10.1016/j.antiviral.2024.106015","DOIUrl":"10.1016/j.antiviral.2024.106015","url":null,"abstract":"<div><div>Substantial reduction of the intact proviral reservoir is essential towards HIV-1 cure. <em>In vivo</em> administration of broadly neutralizing antibodies (bNAbs) targeting the HIV-1 envelope glycoprotein (Env) trimer can decrease the viral reservoir, through Fc-mediated killing of infected cells. In this study, we compared three commonly used antibody engineering strategies to enhance Fc-mediated effector functions: (i) glyco-engineering, (ii) protein engineering, and (iii) subclass/hinge modifications in a panel of anti-HIV-1 antibodies. We found that antibody-dependent cellular phagocytosis (ADCP) was improved by elongating the hinge domain and switching to an IgG3 constant domain. In addition, potent NK cell activation and ADCC activity was observed for afucosylated antibodies and antibodies bearing the GASDALIE mutations. The combination of these engineering strategies further increased NK cell activation and induced antibody dependent cytotoxicity (ADCC) of infected cells at low antibody concentrations. The bNAb N6 was most effective at killing HIV-1 infected cells, likely due to its high affinity and optimal angle of approach. Overall, the findings of this study are applicable to other antibody formats, and can aid the development of effective immunotherapies and antibody-based treatments for HIV-1 cure strategies.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"231 ","pages":"Article 106015"},"PeriodicalIF":4.5,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142340061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-25DOI: 10.1016/j.antiviral.2024.106014
Dvora Joseph Davey , Sumaya Dadan , Kalisha Bheemraj , Catriona Waitt , Saye Khoo , Landon Myer , Lubbe Wiesner , Laura Else , Beth Thompson , Sandra Castel , Nafisa Wara , Peter L. Anderson , Catherine Orrell
Background
There are few data on tenofovir-diphosphate (TFV-DP) concentrations in pregnant and postpartum women on Tenofovir Disoproxil Fumarate-Emtricitabine (TDF-FTC) or Tenofovir Alafenamide-Emtricitabine (TAF-FTC).
Methods
Eligible pregnant women were randomized to TDF-FTC or TAF-FTC and followed for 16 weeks (8-weeks pregnant, 8-weeks postpartum) with weekly collection of dried blood spot (DBS) and 4-weekly peripheral blood mononuclear cells (PBMC). PrEP dosing was observed daily via asynchronous videos sent via cell phone. We report geometric means (GM) and their ratios (GMR) with 95% confidence intervals (CIs) for TFV-DP in PBMC and DBS from pregnancy and postpartum.
Results
We enrolled N = 39 participants (n = 19 TDF-FTC, n = 20 TAF-FTC): median age was 28 years (IQR:25–34); median gestational age was 24-weeks (IQR:21–28). For TDF-FTC, TFV-DP DBS concentrations at 8-weeks did not differ significantly between pregnancy (GM: 675; 95%CI:537–849) and postpartum (GM: 583; 95%CI:471–722; GMR-TDF = 1.16; 95%CI:0.74–1.80). For TAF-FTC, TFV-DP DBS concentrations at 8-weeks were 44% higher in postpartum (GM: 1199; 95%CI:929–1549) versus pregnancy (GM: 832; 95%CI:751–922; GMR-TAF = 1.44; 95% CI: 1.01–2.06). In PBMC analysis of TDF-FTC, 8-week median TFV-DP (pmol/10^6 cell) was 71 (IQR 44–112) in pregnancy and 73 (IQR 50–102) in postpartum (GMR = 1.04; 95%CI:0.44–2.44). In TAF-FTC, median PBMC at 8-weeks was 580 (IQR:341–985) in pregnancy and 666 (IQR:396–1123) in postpartum (GMR = 1.15; 95%CI:0.30–2.49).
Conclusion
TFV-DP concentrations were overall lower during pregnancy than postpartum for TAF-FTC. We found high concentrations of TFV-DP in PBMC in pregnancy and postpartum on TAF-FTC, suggesting PrEP efficacy is maintained. Efficacy and safety studies are warranted to evaluate TAF-FTC for PrEP in pregnant and postpartum women.
{"title":"Evaluation of pharmacokinetics of Tenofovir Alafenamide (TAF) and Tenofovir Disoproxil (TDF) in pregnant and postpartum women in South Africa: PrEP-PP PK study","authors":"Dvora Joseph Davey , Sumaya Dadan , Kalisha Bheemraj , Catriona Waitt , Saye Khoo , Landon Myer , Lubbe Wiesner , Laura Else , Beth Thompson , Sandra Castel , Nafisa Wara , Peter L. Anderson , Catherine Orrell","doi":"10.1016/j.antiviral.2024.106014","DOIUrl":"10.1016/j.antiviral.2024.106014","url":null,"abstract":"<div><h3>Background</h3><div>There are few data on tenofovir-diphosphate (TFV-DP) concentrations in pregnant and postpartum women on Tenofovir Disoproxil Fumarate-Emtricitabine (TDF-FTC) or Tenofovir Alafenamide-Emtricitabine (TAF-FTC).</div></div><div><h3>Methods</h3><div>Eligible pregnant women were randomized to TDF-FTC or TAF-FTC and followed for 16 weeks (8-weeks pregnant, 8-weeks postpartum) with weekly collection of dried blood spot (DBS) and 4-weekly peripheral blood mononuclear cells (PBMC). PrEP dosing was observed daily via asynchronous videos sent via cell phone. We report geometric means (GM) and their ratios (GMR) with 95% confidence intervals (CIs) for TFV-DP in PBMC and DBS from pregnancy and postpartum.</div></div><div><h3>Results</h3><div>We enrolled N = 39 participants (n = 19 TDF-FTC, n = 20 TAF-FTC): median age was 28 years (IQR:25–34); median gestational age was 24-weeks (IQR:21–28). For TDF-FTC, TFV-DP DBS concentrations at 8-weeks did not differ significantly between pregnancy (GM: 675; 95%CI:537–849) and postpartum (GM: 583; 95%CI:471–722; GMR-TDF = 1.16; 95%CI:0.74–1.80). For TAF-FTC, TFV-DP DBS concentrations at 8-weeks were 44% higher in postpartum (GM: 1199; 95%CI:929–1549) versus pregnancy (GM: 832; 95%CI:751–922; GMR-TAF = 1.44; 95% CI: 1.01–2.06). In PBMC analysis of TDF-FTC, 8-week median TFV-DP (pmol/10^6 cell) was 71 (IQR 44–112) in pregnancy and 73 (IQR 50–102) in postpartum (GMR = 1.04; 95%CI:0.44–2.44). In TAF-FTC, median PBMC at 8-weeks was 580 (IQR:341–985) in pregnancy and 666 (IQR:396–1123) in postpartum (GMR = 1.15; 95%CI:0.30–2.49).</div></div><div><h3>Conclusion</h3><div>TFV-DP concentrations were overall lower during pregnancy than postpartum for TAF-FTC. We found high concentrations of TFV-DP in PBMC in pregnancy and postpartum on TAF-FTC, suggesting PrEP efficacy is maintained. Efficacy and safety studies are warranted to evaluate TAF-FTC for PrEP in pregnant and postpartum women.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"231 ","pages":"Article 106014"},"PeriodicalIF":4.5,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142340060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-25DOI: 10.1016/j.antiviral.2024.106012
Demi van der Horst , Madalina E. Carter-Timofte , Adeline Danneels , Leandro Silva da Costa , Naziia Kurmasheva , Anne L. Thielke , Anne Louise Hansen , Vladimir Chorošajev , Christian K. Holm , Sandrine Belouzard , Ivan de Weber , Cedric Beny , David Olagnier
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to the global pandemic of Coronavirus Disease (2019) (COVID-19), underscoring the urgency for effective antiviral drugs. Despite the development of different vaccination strategies, the search for specific antiviral compounds remains crucial. Here, we combine machine learning (ML) techniques with in vitro validation to efficiently identify potential antiviral compounds. We overcome the limited amount of SARS-CoV-2 data available for ML using various techniques, supplemented with data from diverse biomedical assays, which enables end-to-end training of a deep neural network architecture. We use its predictions to identify and prioritize compounds for in vitro testing. Two top-hit compounds, PKI-179 and MTI-31, originally identified as Pi3K-mTORC1/2 pathway inhibitors, exhibit significant antiviral activity against SARS-CoV-2 at low micromolar doses. Notably, both compounds outperform the well-known mTOR inhibitor rapamycin. Furthermore, PKI-179 and MTI-31 demonstrate broad-spectrum antiviral activity against SARS-CoV-2 variants of concern and other coronaviruses. In a physiologically relevant model, both compounds show antiviral effects in primary human airway epithelial (HAE) cultures derived from healthy donors cultured in an air-liquid interface (ALI). This study highlights the potential of ML combined with in vitro testing to expedite drug discovery, emphasizing the adaptability of AI-driven approaches across different viruses, thereby contributing to pandemic preparedness.
{"title":"Large-scale deep learning identifies the antiviral potential of PKI-179 and MTI-31 against coronaviruses","authors":"Demi van der Horst , Madalina E. Carter-Timofte , Adeline Danneels , Leandro Silva da Costa , Naziia Kurmasheva , Anne L. Thielke , Anne Louise Hansen , Vladimir Chorošajev , Christian K. Holm , Sandrine Belouzard , Ivan de Weber , Cedric Beny , David Olagnier","doi":"10.1016/j.antiviral.2024.106012","DOIUrl":"10.1016/j.antiviral.2024.106012","url":null,"abstract":"<div><div>Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to the global pandemic of Coronavirus Disease (2019) (COVID-19), underscoring the urgency for effective antiviral drugs. Despite the development of different vaccination strategies, the search for specific antiviral compounds remains crucial. Here, we combine machine learning (ML) techniques with <em>in vitro</em> validation to efficiently identify potential antiviral compounds. We overcome the limited amount of SARS-CoV-2 data available for ML using various techniques, supplemented with data from diverse biomedical assays, which enables end-to-end training of a deep neural network architecture. We use its predictions to identify and prioritize compounds for <em>in vitro</em> testing. Two top-hit compounds, PKI-179 and MTI-31, originally identified as Pi3K-mTORC1/2 pathway inhibitors, exhibit significant antiviral activity against SARS-CoV-2 at low micromolar doses. Notably, both compounds outperform the well-known mTOR inhibitor rapamycin. Furthermore, PKI-179 and MTI-31 demonstrate broad-spectrum antiviral activity against SARS-CoV-2 variants of concern and other coronaviruses. In a physiologically relevant model, both compounds show antiviral effects in primary human airway epithelial (HAE) cultures derived from healthy donors cultured in an air-liquid interface (ALI). This study highlights the potential of ML combined with <em>in vitro</em> testing to expedite drug discovery, emphasizing the adaptability of AI-driven approaches across different viruses, thereby contributing to pandemic preparedness.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"231 ","pages":"Article 106012"},"PeriodicalIF":4.5,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142327856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-25DOI: 10.1016/j.antiviral.2024.106011
Zhan Gao , Xiaoqing Liu , Yao Lei , Junjun Shao , Guanglei Zhang , Zhuo Hou , Guangqing Zhou , Jin'en Wu , Huichen Guo , Huiyun Chang , Wei Liu
Foot-and-mouth disease (FMD) is a highly contagious and economically devastating viral disease of ruminants and swine, badly affecting the livestock industry worldwide. In clinical practice, vaccination is a frequently employed strategy to prevent foot-and-mouth disease (FMDV). However, commercial inactivated vaccines for FMD mainly rely on humoral immunity, exhibiting poor cellular immune responses and causing adverse reactions. Here, we use the double emulsion method to prepare poly (lactic-co-glycolic acid) nanoparticles (PLGA-NP) encapsulated with IL-2 cytokines, wrap the dendritic cell (DC) membrane carrying FMDV antigen information on the surface of the nanoparticles, obtaining a biomimetic nanoparticle vaccine Biom@DC with uniform size. This vaccine can effortlessly move through lymph nodes due to its nanoscale size advantage. It also possesses DC ability to present antigens, and antigen presentation can be made more effective with high biocompatibility. The sustained release of IL-2 encapsulated in the core of PLGA-NP in vivo can effectively promote the body's cellular immune response. Immune tests on mice have shown that Biom@DC may greatly increase T cell activation and proliferation both in vivo and in vitro, while also significantly reducing the fraction of inhibitory Treg cells. Furthermore, in the micro serum neutralization assay for FMDV, it has been demonstrated that the group vaccinated with Biom@DC exhibits a clear neutralizing effect. Given its strong immunogenicity, Biom@DC has the potential to develop into a novel, potent anti-FMDV vaccination.
{"title":"Dendritic cell-based biomimetic nanoparticles for foot-and-mouth disease induce robust cellular immunity","authors":"Zhan Gao , Xiaoqing Liu , Yao Lei , Junjun Shao , Guanglei Zhang , Zhuo Hou , Guangqing Zhou , Jin'en Wu , Huichen Guo , Huiyun Chang , Wei Liu","doi":"10.1016/j.antiviral.2024.106011","DOIUrl":"10.1016/j.antiviral.2024.106011","url":null,"abstract":"<div><div>Foot-and-mouth disease (FMD) is a highly contagious and economically devastating viral disease of ruminants and swine, badly affecting the livestock industry worldwide. In clinical practice, vaccination is a frequently employed strategy to prevent foot-and-mouth disease (FMDV). However, commercial inactivated vaccines for FMD mainly rely on humoral immunity, exhibiting poor cellular immune responses and causing adverse reactions. Here, we use the double emulsion method to prepare poly (lactic-co-glycolic acid) nanoparticles (PLGA-NP) encapsulated with IL-2 cytokines, wrap the dendritic cell (DC) membrane carrying FMDV antigen information on the surface of the nanoparticles, obtaining a biomimetic nanoparticle vaccine Biom@DC with uniform size. This vaccine can effortlessly move through lymph nodes due to its nanoscale size advantage. It also possesses DC ability to present antigens, and antigen presentation can be made more effective with high biocompatibility. The sustained release of IL-2 encapsulated in the core of PLGA-NP <em>in vivo</em> can effectively promote the body's cellular immune response. Immune tests on mice have shown that Biom@DC may greatly increase T cell activation and proliferation both <em>in vivo</em> and <em>in vitro</em>, while also significantly reducing the fraction of inhibitory Treg cells. Furthermore, in the micro serum neutralization assay for FMDV, it has been demonstrated that the group vaccinated with Biom@DC exhibits a clear neutralizing effect. Given its strong immunogenicity, Biom@DC has the potential to develop into a novel, potent anti-FMDV vaccination.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"231 ","pages":"Article 106011"},"PeriodicalIF":4.5,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142324106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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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