Pub Date : 2025-02-01DOI: 10.1016/j.antiviral.2024.106053
Johannes Lang , Sudip Kumar Dutta , Mila M. Leuthold , Lisa Reichert , Nikos Kühl , Byron Martina , Christian D. Klein
The viral NS2B-NS3 protease is a promising drug target to combat dengue virus (DENV) and other emerging flaviviruses. The discovery of novel DENV protease inhibitors with antiviral efficacy is hampered by the low predictive power of biochemical assays. We herein present a comparative evaluation of biochemical DENV protease assay conditions and their benchmarking against antiviral efficacy and a protease-specific reporter gene assay. Variations were performed with respect to pH, type of detergent, buffer, and substrate. The revised assay conditions were applied in a medicinal chemistry effort aimed at phenylglycine protease inhibitors. This validation study demonstrated a considerably improved predictive power for antiviral efficacy in comparison to previous approaches. An extensive evaluation of phenylglycine-based DENV protease inhibitors with highly diverse N-terminal caps indicates further development potential in this structural region. Furthermore, the phenylglycine moiety may be less essential than previously assumed, providing a development option towards reduced lipophilicity and thereby an improved pharmacokinetic and toxicity profile.
{"title":"Antiviral drug discovery with an optimized biochemical dengue protease assay: Improved predictive power for antiviral efficacy","authors":"Johannes Lang , Sudip Kumar Dutta , Mila M. Leuthold , Lisa Reichert , Nikos Kühl , Byron Martina , Christian D. Klein","doi":"10.1016/j.antiviral.2024.106053","DOIUrl":"10.1016/j.antiviral.2024.106053","url":null,"abstract":"<div><div>The viral NS2B-NS3 protease is a promising drug target to combat dengue virus (DENV) and other emerging flaviviruses. The discovery of novel DENV protease inhibitors with antiviral efficacy is hampered by the low predictive power of biochemical assays. We herein present a comparative evaluation of biochemical DENV protease assay conditions and their benchmarking against antiviral efficacy and a protease-specific reporter gene assay. Variations were performed with respect to pH, type of detergent, buffer, and substrate. The revised assay conditions were applied in a medicinal chemistry effort aimed at phenylglycine protease inhibitors. This validation study demonstrated a considerably improved predictive power for antiviral efficacy in comparison to previous approaches. An extensive evaluation of phenylglycine-based DENV protease inhibitors with highly diverse N-terminal caps indicates further development potential in this structural region. Furthermore, the phenylglycine moiety may be less essential than previously assumed, providing a development option towards reduced lipophilicity and thereby an improved pharmacokinetic and toxicity profile.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"234 ","pages":"Article 106053"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790999","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 : 2025-01-30DOI: 10.1016/j.antiviral.2025.106096
Svenja Weiss , Raymond A. Alvarez , Marisa Goff , Hongru Li , Eric Acosta , Ping Chen , Helen M. Seedhom , Talia H. Swartz , Margaret Gartland , Andrew Clark , Judith A. Aberg , Benjamin K. Chen
Fostemsavir (FTR) is an approved first-in-class small molecule Env antagonist for treating multi-drug resistant (MDR) HIV-1 infection. In the BRIGHTE study, viral suppression rates in heavily treatment-experienced people with HIV (PWH) increased from week 48 through week 96. Factors that contribute to this late response are not well understood. Given FTR's ability to stabilize a native HIV-1 envelope trimer conformational state, we examined anti-HIV humoral immune responses in the BRIGHTE study to explore how evolving antibody responses in the presence of drug correlate with delayed viral suppression. 16 BRIGHTE study participants (ppt) were selected based on their time to first viremic suppression: eight early (EVS) and eight late viral suppressors (LVS). Immune responses were also analyzed in eight ppt from the SAILING study that evaluated dolutegravir. Anti-HIV Env IgG titer, cell-free and cell-to-cell neutralization activity, FcγRIIa- and FcγRIIIa-signaling, and plasma cytokines at weeks 0, 4 and 108 were examined and correlated with clinical variables associated with treatment response. FTR treatment did not significantly enhance antibody responses against reference strain of HIV in LVS compared to EVS. However, at baseline, LVS had significantly lower anti-HIV IgG titers, higher VL, lower CD4+ T-cell counts and experienced greater increases in CD4+ T-cell counts than EVS. Additionally, IL-8 levels were increased in LVS vs. EVS at treatment initiation. In comparison, SAILING ppt showed increased FcγRIIa signaling during drug treatment compared to the FTR groups. Further studies will determine if pre-treatment characteristics influence timing to viral suppression in FTR-treated individuals with MDR-HIV.
{"title":"High HIV-1 viremia and low anti-Env antibody responses are associated with delayed treatment response to fostemsavir in highly treatment-experienced individuals","authors":"Svenja Weiss , Raymond A. Alvarez , Marisa Goff , Hongru Li , Eric Acosta , Ping Chen , Helen M. Seedhom , Talia H. Swartz , Margaret Gartland , Andrew Clark , Judith A. Aberg , Benjamin K. Chen","doi":"10.1016/j.antiviral.2025.106096","DOIUrl":"10.1016/j.antiviral.2025.106096","url":null,"abstract":"<div><div>Fostemsavir (FTR) is an approved first-in-class small molecule Env antagonist for treating multi-drug resistant (MDR) HIV-1 infection. In the BRIGHTE study, viral suppression rates in heavily treatment-experienced people with HIV (PWH) increased from week 48 through week 96. Factors that contribute to this late response are not well understood. Given FTR's ability to stabilize a native HIV-1 envelope trimer conformational state, we examined anti-HIV humoral immune responses in the BRIGHTE study to explore how evolving antibody responses in the presence of drug correlate with delayed viral suppression. 16 BRIGHTE study participants (ppt) were selected based on their time to first viremic suppression: eight early (EVS) and eight late viral suppressors (LVS). Immune responses were also analyzed in eight ppt from the SAILING study that evaluated dolutegravir. Anti-HIV Env IgG titer, cell-free and cell-to-cell neutralization activity, FcγRIIa- and FcγRIIIa-signaling, and plasma cytokines at weeks 0, 4 and 108 were examined and correlated with clinical variables associated with treatment response. FTR treatment did not significantly enhance antibody responses against reference strain of HIV in LVS compared to EVS. However, at baseline, LVS had significantly lower anti-HIV IgG titers, higher VL, lower CD4<sup>+</sup> T-cell counts and experienced greater increases in CD4<sup>+</sup> T-cell counts than EVS. Additionally, IL-8 levels were increased in LVS vs. EVS at treatment initiation. In comparison, SAILING ppt showed increased FcγRIIa signaling during drug treatment compared to the FTR groups. Further studies will determine if pre-treatment characteristics influence timing to viral suppression in FTR-treated individuals with MDR-HIV.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"235 ","pages":"Article 106096"},"PeriodicalIF":4.5,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073759","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 : 2025-01-30DOI: 10.1016/j.antiviral.2025.106098
Paul T. Winnard Jr. , Farhad Vesuna , Venu Raman
Viruses have co-evolved with their hosts, intertwining their life cycles. As a result, components and pathways from a host cell's processes are appropriated for virus infection. This review examines the host DExD-box RNA helicases known to influence virus infection during human infections. We have identified 42 species of viruses (28 genera and 21 families) whose life cycles are modulated by at least one, but often multiple, DExD-box RNA helicases. Of these, 37 species require one or multiple DExD-box RNA helicases for efficient infections, i.e., in these cases the DExD-box RNA helicases are pro-viral. However, similar evolutionary processes have also led to cellular responses that combat viral infections. In humans, these responses comprise intrinsic and innate immune responses initiated and regulated by some of the same DExD-box RNA helicases that act as pro-viral helicases. Currently, anti-viral DExD-box RNA helicase responses to viral infections are noted in 23 viral species. Notably, most studied viruses are linked to severe, life-threatening diseases, leading many researchers to focus on DExD-box RNA helicases as potential therapeutic targets. Thus, we present examples of host-directed therapies targeting anti-viral DExD-box RNA helicases. Overall, our findings indicate that various DExD-box RNA helicases serve as either pro- and/or anti-viral agents across a wide range of viruses. Continued investigation into the pro-viral activities of these helicases will help identify specific protein motifs that can be targeted by drugs to manage or eliminate the severe diseases caused by these viruses. Comparative studies on anti-viral DExD-box RNA helicase responses may also offer insights for developing therapies that enhance immune responses triggered by these helicases.
{"title":"DExD-box RNA helicases in human viral infections: Pro- and anti-viral functions","authors":"Paul T. Winnard Jr. , Farhad Vesuna , Venu Raman","doi":"10.1016/j.antiviral.2025.106098","DOIUrl":"10.1016/j.antiviral.2025.106098","url":null,"abstract":"<div><div>Viruses have co-evolved with their hosts, intertwining their life cycles. As a result, components and pathways from a host cell's processes are appropriated for virus infection. This review examines the host DExD-box RNA helicases known to influence virus infection during human infections. We have identified 42 species of viruses (28 genera and 21 families) whose life cycles are modulated by at least one, but often multiple, DExD-box RNA helicases. Of these, 37 species require one or multiple DExD-box RNA helicases for efficient infections, i.e., in these cases the DExD-box RNA helicases are pro-viral. However, similar evolutionary processes have also led to cellular responses that combat viral infections. In humans, these responses comprise intrinsic and innate immune responses initiated and regulated by some of the same DExD-box RNA helicases that act as pro-viral helicases. Currently, anti-viral DExD-box RNA helicase responses to viral infections are noted in 23 viral species. Notably, most studied viruses are linked to severe, life-threatening diseases, leading many researchers to focus on DExD-box RNA helicases as potential therapeutic targets. Thus, we present examples of host-directed therapies targeting anti-viral DExD-box RNA helicases. Overall, our findings indicate that various DExD-box RNA helicases serve as either pro- and/or anti-viral agents across a wide range of viruses. Continued investigation into the pro-viral activities of these helicases will help identify specific protein motifs that can be targeted by drugs to manage or eliminate the severe diseases caused by these viruses. Comparative studies on anti-viral DExD-box RNA helicase responses may also offer insights for developing therapies that enhance immune responses triggered by these helicases.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"235 ","pages":"Article 106098"},"PeriodicalIF":4.5,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073757","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}
The impact of treatment-emergent amino acid substitutions (TEAASs) in severe acute coronavirus 2 (SARS-CoV-2) 3C-like protease (3CLpro) on clinical and virologic outcomes was evaluated in patients with mild-to-moderate coronavirus disease 2019 (COVID-19) who received ensitrelvir 125 mg in the SCORPIO-SR trial. Individuals were randomised to ensitrelvir or matched placebo once daily for 5 days (first dose <72 h after disease onset). 3CLpro-TEAASs were identified by sequencing nsp5 encoding 3CLpro from pre- and post-treatment nasopharyngeal swabs. Time to resolution of a composite of five characteristic COVID-19 symptoms (TTR) was compared between patients with and without the most common 3CLpro-TEAASs in the ensitrelvir arm. The ensitrelvir and placebo intention-to-treat populations comprised 345 and 341 patients, respectively. 3CLpro-TEAASs were detected in 19/204 (9.3%) ensitrelvir-treated and 3/137 (2.2%) placebo-treated patients with paired sequence data. The most common 3CLpro-TEAASs in the ensitrelvir arm were M49L (n = 12), M49I (n = 3) and S144A (n = 2). In the placebo arm, all 3CLpro-TEAASs occurred in ≤1 patient. Median (95% confidence interval) TTR was comparable between patients with and without those TEAASs (158.8 h [112.1–281.9] vs 189.7 h [151.4–234.4]). Mean viral RNA levels declined more slowly in patients with M49L/I or S144A versus those without. Reductions in viral titre were unaffected by these TEAASs. The characteristics of recombinant SARS-CoV-2 with 3CLpro mutations were explored in vitro. Recombinant viruses with some 3CLpro mutations had reduced susceptibility to ensitrelvir in vitro, with limited effects on viral and competitive fitness. Continued surveillance is warranted to monitor the spread of viruses with 3CLpro mutations.
{"title":"Ensitrelvir treatment–emergent amino acid substitutions in SARS-CoV-2 3CLpro detected in the SCORPIO-SR phase 3 trial","authors":"Takeki Uehara , Hiroshi Yotsuyanagi , Norio Ohmagari , Yohei Doi , Masaya Yamato , Takumi Imamura , Hiroki Sakaguchi , Akimasa Fukushi , Yosuke Takeda , Keiko Baba , Haruaki Nobori , Tadashi Miyamoto , Shuhei Arita , Reiko Dodo , Alice Shimba , Keita Fukao , Takao Shishido , Yuko Tsuge , Hiroshi Mukae","doi":"10.1016/j.antiviral.2025.106097","DOIUrl":"10.1016/j.antiviral.2025.106097","url":null,"abstract":"<div><div>The impact of treatment-emergent amino acid substitutions (TEAASs) in severe acute coronavirus 2 (SARS-CoV-2) 3C-like protease (3CL<sup>pro</sup>) on clinical and virologic outcomes was evaluated in patients with mild-to-moderate coronavirus disease 2019 (COVID-19) who received ensitrelvir 125 mg in the SCORPIO-SR trial. Individuals were randomised to ensitrelvir or matched placebo once daily for 5 days (first dose <72 h after disease onset). 3CL<sup>pro</sup>-TEAASs were identified by sequencing <em>nsp5</em> encoding 3CL<sup>pro</sup> from pre- and post-treatment nasopharyngeal swabs. Time to resolution of a composite of five characteristic COVID-19 symptoms (TTR) was compared between patients with and without the most common 3CL<sup>pro</sup>-TEAASs in the ensitrelvir arm. The ensitrelvir and placebo intention-to-treat populations comprised 345 and 341 patients, respectively. 3CL<sup>pro</sup>-TEAASs were detected in 19/204 (9.3%) ensitrelvir-treated and 3/137 (2.2%) placebo-treated patients with paired sequence data. The most common 3CL<sup>pro</sup>-TEAASs in the ensitrelvir arm were M49L (n = 12), M49I (n = 3) and S144A (n = 2). In the placebo arm, all 3CL<sup>pro</sup>-TEAASs occurred in ≤1 patient. Median (95% confidence interval) TTR was comparable between patients with and without those TEAASs (158.8 h [112.1–281.9] vs 189.7 h [151.4–234.4]). Mean viral RNA levels declined more slowly in patients with M49L/I or S144A versus those without. Reductions in viral titre were unaffected by these TEAASs. The characteristics of recombinant SARS-CoV-2 with 3CL<sup>pro</sup> mutations were explored <em>in vitro</em>. Recombinant viruses with some 3CL<sup>pro</sup> mutations had reduced susceptibility to ensitrelvir <em>in vitro</em>, with limited effects on viral and competitive fitness. Continued surveillance is warranted to monitor the spread of viruses with 3CL<sup>pro</sup> mutations.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"236 ","pages":"Article 106097"},"PeriodicalIF":4.5,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073758","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 : 2025-01-27DOI: 10.1016/j.antiviral.2025.106092
Qian Wu , Hairuo Wu , Yabin Hu , Xingyu Zheng , Fangfang Chang , Yongchen Liu , Zhendong Pan , Qijie Wang , Fei Tang , Jun Qian , Yuezhou Li , Bin Huang , Keqiu Chen , Juan Xu , You Wang , Xiangping Xie , Ping Zhao , Xu Wu , Xiaowang Qu , Yi-Ping Li
The Omicron BA.2.86 subvariants, JN.1, KP.2, and KP.3, have become predominant globally, raising concerns about their immune evasion from vaccines and monoclonal antibody (mAb) treatments. These variants harbor more receptor-binding domain (RBD) mutations than the XBB and EG.5 sub-lineages, which are already known to compromise vaccine and therapeutic efficacy. We evaluated sera from individuals vaccinated with inactivated vaccines, with or without breakthrough infections, as well as COVID-19 convalescents. Our results showed a substantial decrease in serum neutralizing activity against the JN.1, KP.2, XBB.1.5, and EG.5.1 variants compared to BA.2. Additionally, we developed 19 neutralizing antibodies from memory B cells, with some retaining efficacy against earlier Omicron variants. However, potency was notably diminished against newer subvariants like BF.7, BQ.1, XBB.1.5, and BA.2.86. Of mAbs, those isolated from COVID-19 convalescents, particularly SA-3, exhibited exceptional potency across ten variants from BA.2 to KP.2, with IC50 values ranging from 0.006 to 2.546 μg/mL. However, SA-3 had lost neutralizing activity against the KP.3 due to the Q493E mutation, but the KP.3 became susceptible to neutralization by the other mAb, SA-6. In contrast, SA-6 was unable to neutralize KP.2 because of the presence of R346T mutation. Our findings underscore the importance of continuous surveillance of viral evolution and the need for updated vaccines and therapeutics to combat the ongoing evolution of SARS-CoV-2, particularly in the context of emerging variants that escape both vaccine-induced immunity and monoclonal antibody treatments.
{"title":"Immune evasion of Omicron variants JN.1, KP.2, and KP.3 to the polyclonal and monoclonal antibodies from COVID-19 convalescents and vaccine recipients","authors":"Qian Wu , Hairuo Wu , Yabin Hu , Xingyu Zheng , Fangfang Chang , Yongchen Liu , Zhendong Pan , Qijie Wang , Fei Tang , Jun Qian , Yuezhou Li , Bin Huang , Keqiu Chen , Juan Xu , You Wang , Xiangping Xie , Ping Zhao , Xu Wu , Xiaowang Qu , Yi-Ping Li","doi":"10.1016/j.antiviral.2025.106092","DOIUrl":"10.1016/j.antiviral.2025.106092","url":null,"abstract":"<div><div>The Omicron BA.2.86 subvariants, JN.1, KP.2, and KP.3, have become predominant globally, raising concerns about their immune evasion from vaccines and monoclonal antibody (mAb) treatments. These variants harbor more receptor-binding domain (RBD) mutations than the XBB and EG.5 sub-lineages, which are already known to compromise vaccine and therapeutic efficacy. We evaluated sera from individuals vaccinated with inactivated vaccines, with or without breakthrough infections, as well as COVID-19 convalescents. Our results showed a substantial decrease in serum neutralizing activity against the JN.1, KP.2, XBB.1.5, and EG.5.1 variants compared to BA.2. Additionally, we developed 19 neutralizing antibodies from memory B cells, with some retaining efficacy against earlier Omicron variants. However, potency was notably diminished against newer subvariants like BF.7, BQ.1, XBB.1.5, and BA.2.86. Of mAbs, those isolated from COVID-19 convalescents, particularly SA-3, exhibited exceptional potency across ten variants from BA.2 to KP.2, with IC50 values ranging from 0.006 to 2.546 μg/mL. However, SA-3 had lost neutralizing activity against the KP.3 due to the Q493E mutation, but the KP.3 became susceptible to neutralization by the other mAb, SA-6. In contrast, SA-6 was unable to neutralize KP.2 because of the presence of R346T mutation. Our findings underscore the importance of continuous surveillance of viral evolution and the need for updated vaccines and therapeutics to combat the ongoing evolution of SARS-CoV-2, particularly in the context of emerging variants that escape both vaccine-induced immunity and monoclonal antibody treatments.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"235 ","pages":"Article 106092"},"PeriodicalIF":4.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045446","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 : 2025-01-25DOI: 10.1016/j.antiviral.2025.106095
Olivier Reynard , Mathieu Iampietro , Claire Dumont , Sandrine Le Guellec , Stephanie Durand , Marie Moroso , Elise Brisebard , Kévin P. Dhondt , Rodolphe Pelissier , Cyrille Mathieu , Maria Cabrera , Deborah Le Pennec , Lucia Amurri , Christopher Alabi , Sylvain Cardinaud , Matteo Porotto , Anne Moscona , Laurent Vecellio , Branka Horvat
Nipah virus (NiV) is a lethal zoonotic paramyxovirus that can be transmitted from person to person through the respiratory route. There are currently no licensed vaccines or therapeutics. A lipopeptide-based fusion inhibitor was developed and previously evaluated for efficacy against the NiV-Malaysia strain. Intraperitoneal administration in hamsters showed superb prophylactic activity and promising efficacy, however the intratracheal delivery mode in non-human primates proved intractable and spurred the development of an aerosolized delivery route that could be clinically applicable. We developed an aerosol delivery system in an artificial respiratory 3D model and optimized the combinations of flow rate and particle size for lung deposition. We characterized the nebulizer device and assessed the safety of lipopeptide nebulization in an African green monkey model that mimics human NiV infection. Three nebulized doses of fusion-inhibitory lipopeptide were administered every 24 h, resulting in peptide deposition across multiple regions of both lungs without causing toxicity or adverse hematological and biochemical effects. In peptide-treated monkeys challenged with a lethal dose of NiV-Bangladesh, animals retained robust levels of T and B-lymphocytes in the blood, infection-induced lethality was significantly delayed, and 2 out of 5 monkeys were protected from NiV infection. The present study establishes the safety and feasibility of the nebulizer delivery method for AGM studies. Future studies will compare delivery methods using next-generation fusion-inhibitory anti-NiV lipopeptides to evaluate the potential role of this aerosol delivery approach in achieving a rapid antiviral response.
{"title":"Development of nebulized inhalation delivery for fusion-inhibitory lipopeptides to protect non-human primates against Nipah-Bangladesh infection","authors":"Olivier Reynard , Mathieu Iampietro , Claire Dumont , Sandrine Le Guellec , Stephanie Durand , Marie Moroso , Elise Brisebard , Kévin P. Dhondt , Rodolphe Pelissier , Cyrille Mathieu , Maria Cabrera , Deborah Le Pennec , Lucia Amurri , Christopher Alabi , Sylvain Cardinaud , Matteo Porotto , Anne Moscona , Laurent Vecellio , Branka Horvat","doi":"10.1016/j.antiviral.2025.106095","DOIUrl":"10.1016/j.antiviral.2025.106095","url":null,"abstract":"<div><div>Nipah virus (NiV) is a lethal zoonotic paramyxovirus that can be transmitted from person to person through the respiratory route. There are currently no licensed vaccines or therapeutics. A lipopeptide-based fusion inhibitor was developed and previously evaluated for efficacy against the NiV-Malaysia strain. Intraperitoneal administration in hamsters showed superb prophylactic activity and promising efficacy, however the intratracheal delivery mode in non-human primates proved intractable and spurred the development of an aerosolized delivery route that could be clinically applicable. We developed an aerosol delivery system in an artificial respiratory 3D model and optimized the combinations of flow rate and particle size for lung deposition. We characterized the nebulizer device and assessed the safety of lipopeptide nebulization in an African green monkey model that mimics human NiV infection. Three nebulized doses of fusion-inhibitory lipopeptide were administered every 24 h, resulting in peptide deposition across multiple regions of both lungs without causing toxicity or adverse hematological and biochemical effects. In peptide-treated monkeys challenged with a lethal dose of NiV-Bangladesh, animals retained robust levels of T and B-lymphocytes in the blood, infection-induced lethality was significantly delayed, and 2 out of 5 monkeys were protected from NiV infection. The present study establishes the safety and feasibility of the nebulizer delivery method for AGM studies. Future studies will compare delivery methods using next-generation fusion-inhibitory anti-NiV lipopeptides to evaluate the potential role of this aerosol delivery approach in achieving a rapid antiviral response.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"235 ","pages":"Article 106095"},"PeriodicalIF":4.5,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051338","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 : 2025-01-22DOI: 10.1016/j.antiviral.2025.106093
Ziying Liu , Guiping Li , Xiaoran Li , Yiran Wang , Leyi Liao , Ti Yang , Chao Han , Kuiyuan Huang , Chuyuan Chen , Xuanyi Li , Hongyan Liu , Xiaoyong Zhang
Background & aims
Chronic hepatitis B (CHB) arises from a persistent hepatitis B virus (HBV) infection, complicating efforts for a functional cure. Kupffer cells (KCs), liver-resident macrophages, are pivotal in mediating immune tolerance to HBV. Although CD163 marks M2-polarized KCs, its precise role in HBV infection remains unclear and warrants further investigation.
Methods
CD163 expression in liver tissues of patients with CHB was analyzed using the Gene Expression Omnibus (GEO) database. Cd163 knockout mice were utilized to establish HBV-persistent mouse model, and CD163 deficiency effect on HBV viral markers and T cell immune responses were examined in vivo and in vitro.
Results
CD163 expression was elevated and correlated with ALT levels in the liver of patients with CHB. In HBV-persistent mouse model, CD163 deficiency facilitated the clearance of HBsAg, HBeAg, HBV DNA, and HBcAg. Additionally, CD163 deficiency promoted the differentiation of naïve T cells into HBV-specific effector T cells. Further, we found that CD163 deficiency reduces KCs-derived IL-10 secretion, and blocking IL-10 further strengthens the enhanced HBV-specific T cell response due to CD163 deficiency.
Conclusions
Our findings indicate that CD163 deficiency enhances the HBV-specific T cell response, thereby facilitating HBV clearance through reducing KCs-derived IL-10 secretion. This suggests that CD163 may serve as a potential target for the restoration of exhausted T cell function.
{"title":"CD163 impairs HBV clearance in mice by regulating intrahepatic T cell immune response via an IL-10-dependent mechanism","authors":"Ziying Liu , Guiping Li , Xiaoran Li , Yiran Wang , Leyi Liao , Ti Yang , Chao Han , Kuiyuan Huang , Chuyuan Chen , Xuanyi Li , Hongyan Liu , Xiaoyong Zhang","doi":"10.1016/j.antiviral.2025.106093","DOIUrl":"10.1016/j.antiviral.2025.106093","url":null,"abstract":"<div><h3>Background & aims</h3><div>Chronic hepatitis B (CHB) arises from a persistent hepatitis B virus (HBV) infection, complicating efforts for a functional cure. Kupffer cells (KCs), liver-resident macrophages, are pivotal in mediating immune tolerance to HBV. Although CD163 marks M2-polarized KCs, its precise role in HBV infection remains unclear and warrants further investigation.</div></div><div><h3>Methods</h3><div>CD163 expression in liver tissues of patients with CHB was analyzed using the Gene Expression Omnibus (GEO) database. <em>Cd163</em> knockout mice were utilized to establish HBV-persistent mouse model, and CD163 deficiency effect on HBV viral markers and T cell immune responses were examined <em>in vivo</em> and <em>in vitro</em>.</div></div><div><h3>Results</h3><div>CD163 expression was elevated and correlated with ALT levels in the liver of patients with CHB. In HBV-persistent mouse model, CD163 deficiency facilitated the clearance of HBsAg, HBeAg, HBV DNA, and HBcAg. Additionally, CD163 deficiency promoted the differentiation of naïve T cells into HBV-specific effector T cells. Further, we found that CD163 deficiency reduces KCs-derived IL-10 secretion, and blocking IL-10 further strengthens the enhanced HBV-specific T cell response due to CD163 deficiency.</div></div><div><h3>Conclusions</h3><div>Our findings indicate that CD163 deficiency enhances the HBV-specific T cell response, thereby facilitating HBV clearance through reducing KCs-derived IL-10 secretion. This suggests that CD163 may serve as a potential target for the restoration of exhausted T cell function.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"235 ","pages":"Article 106093"},"PeriodicalIF":4.5,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143036222","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 : 2025-01-17DOI: 10.1016/j.antiviral.2025.106082
Mengxin Xu , Zhaoyong Zhang , Yuzhu Sun , Haoting Mai , Siqi Liu , Shuning Liu , Kexin Lv , Feiyang Yu , Yuanyuan Wang , Xinyu Yue , Jiayi Zhang , Xiaoyu Cai , Ruixin Zhao , Hongjie Lu , Lin Liu , Huanle Luo , Haiyan Zhao , Yanqun Wang , Peng Gong , Shoudeng Chen , Yao-Qing Chen
IgA antibodies are critical components of the mucosal immune barrier, providing essential first-line defense against viral infections. In this study, we investigated the impact of antibody class switching on neutralization efficacy by engineering recombinant antibodies of different isotypes (IgA1, IgG1) with identical variable regions from SARS-CoV-2 convalescent patients. A potent, broad-spectrum neutralizing monoclonal antibody CAV-C65 exhibited a ten-fold increase in neutralization potency upon switching from IgG1 to IgA1 monomer. Structural analysis revealed that this antibody binds to two adjacent receptor binding domains on the spike protein. Enhanced neutralization by IgA1 was attributed to the combined effects of increased affinity, unique hinge region properties, and potential cross-linking of viral particles. Inhaled CAV-C65 IgA1 demonstrated prophylactic efficacy against lethal SARS-CoV-2 infection in hACE2 mice. These findings highlight the pivotal role of IgA in antiviral immunity and inform the development of IgA-based therapeutics.
{"title":"IgA class switching enhances neutralizing potency against SARS-CoV-2 by increased antibody hinge flexibility","authors":"Mengxin Xu , Zhaoyong Zhang , Yuzhu Sun , Haoting Mai , Siqi Liu , Shuning Liu , Kexin Lv , Feiyang Yu , Yuanyuan Wang , Xinyu Yue , Jiayi Zhang , Xiaoyu Cai , Ruixin Zhao , Hongjie Lu , Lin Liu , Huanle Luo , Haiyan Zhao , Yanqun Wang , Peng Gong , Shoudeng Chen , Yao-Qing Chen","doi":"10.1016/j.antiviral.2025.106082","DOIUrl":"10.1016/j.antiviral.2025.106082","url":null,"abstract":"<div><div>IgA antibodies are critical components of the mucosal immune barrier, providing essential first-line defense against viral infections. In this study, we investigated the impact of antibody class switching on neutralization efficacy by engineering recombinant antibodies of different isotypes (IgA1, IgG1) with identical variable regions from SARS-CoV-2 convalescent patients. A potent, broad-spectrum neutralizing monoclonal antibody CAV-C65 exhibited a ten-fold increase in neutralization potency upon switching from IgG1 to IgA1 monomer. Structural analysis revealed that this antibody binds to two adjacent receptor binding domains on the spike protein. Enhanced neutralization by IgA1 was attributed to the combined effects of increased affinity, unique hinge region properties, and potential cross-linking of viral particles. Inhaled CAV-C65 IgA1 demonstrated prophylactic efficacy against lethal SARS-CoV-2 infection in hACE2 mice. These findings highlight the pivotal role of IgA in antiviral immunity and inform the development of IgA-based therapeutics.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"235 ","pages":"Article 106082"},"PeriodicalIF":4.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998930","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 : 2025-01-16DOI: 10.1016/j.antiviral.2025.106081
Huiqiang Wang , Boming Cui , Haiyan Yan , Shuo Wu , Kun Wang , Ge Yang , Jiandong Jiang , Yuhuan Li
Our previous study had found that cellular pseudokinase tribbles 3 (TRIB3) facilitates the infection of enterovirus A71 (EV-A71) via upregulating the protein level of EV-A71 receptor scavenger receptor class B member 2 (SCARB2). In the present study, we used metformin, which had been reported to down-regulate TRIB3 expression, to verify the potential of TRIB3 as an antiviral target. Here, we found that metformin can indeed impede the replication of EV-A71 and Coxsackievirus A16 (CVA16) through inhibiting the transcription of TRIB3 to indirectly down-regulate SCARB2 protein levels to block viral infection. Importantly, we also found that metformin can inhibit the replication of EV-A71 and CVA16 in a TRIB3-independent manner. In fact, we found that both metformin and cellular AMP-activated protein kinase (AMPK) agonist AICAR can inhibit the replication of EV-A71 and CVA16 by pharmacologically activating AMPK. Moreover, AMPK phosphorylation specific inhibitor Compound C treatment can reverse the antiviral effect of metformin, indicating that metformin can indeed play an antiviral role through regulating AMPK. More importantly, we confirmed that metformin could effectively protected mice from lethal EV-A71 infection. Metformin treatment decreased the levels of EV-A71 VP1 protein and viral RNA in the infected muscles, and improved muscle pathology. These findings suggest that TRIB3 does have potential as a target for antiviral drugs, and metformin may be a potential agent or supplement against enterovirus infection.
{"title":"Metformin inhibits EV-A71 and CVA16 infections by regulating TRIB3-SCARB2 axis and activating AMPK","authors":"Huiqiang Wang , Boming Cui , Haiyan Yan , Shuo Wu , Kun Wang , Ge Yang , Jiandong Jiang , Yuhuan Li","doi":"10.1016/j.antiviral.2025.106081","DOIUrl":"10.1016/j.antiviral.2025.106081","url":null,"abstract":"<div><div>Our previous study had found that cellular pseudokinase tribbles 3 (TRIB3) facilitates the infection of enterovirus A71 (EV-A71) via upregulating the protein level of EV-A71 receptor scavenger receptor class B member 2 (SCARB2). In the present study, we used metformin, which had been reported to down-regulate TRIB3 expression, to verify the potential of TRIB3 as an antiviral target. Here, we found that metformin can indeed impede the replication of EV-A71 and Coxsackievirus A16 (CVA16) through inhibiting the transcription of TRIB3 to indirectly down-regulate SCARB2 protein levels to block viral infection. Importantly, we also found that metformin can inhibit the replication of EV-A71 and CVA16 in a TRIB3-independent manner. In fact, we found that both metformin and cellular AMP-activated protein kinase (AMPK) agonist AICAR can inhibit the replication of EV-A71 and CVA16 by pharmacologically activating AMPK. Moreover, AMPK phosphorylation specific inhibitor Compound C treatment can reverse the antiviral effect of metformin, indicating that metformin can indeed play an antiviral role through regulating AMPK. More importantly, we confirmed that metformin could effectively protected mice from lethal EV-A71 infection. Metformin treatment decreased the levels of EV-A71 VP1 protein and viral RNA in the infected muscles, and improved muscle pathology. These findings suggest that TRIB3 does have potential as a target for antiviral drugs, and metformin may be a potential agent or supplement against enterovirus infection.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"235 ","pages":"Article 106081"},"PeriodicalIF":4.5,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998941","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 : 2025-01-01DOI: 10.1016/j.antiviral.2024.106059
Binbin Wang , Hongjie Xia , Bi-Hung Peng , Eun-Jin Choi , Bing Tian , Xuping Xie , Shinji Makino , Xiaoyong Bao , Pei-Yong Shi , Vineet Menachery , Tian Wang
Enhanced expression of Pellino-1 (Peli1), a ubiquitin ligase is known to be associated with COVID-19 susceptibility. The underlying mechanisms are not known. Here, we report that mice deficient in Peli1 (Peli1−/−) had reduced viral load and attenuated inflammatory immune responses and tissue damage in the lung following SARS-CoV-2 infection. Overexpressing Peli1 in 293 T cells increased SARS-CoV-2 infection via promoting virus replication and transcription, without affecting virus attachment and entry into the cells. Smaducin-6 treatment which is known to disrupt Peli1-mediated NF-KB activation, attenuated inflammatory immune responses in human lung epithelial cells as well as in the lung of K18-hACE2 mice following SARS-CoV-2 infection, though it had minimal effects on SARS-CoV-2 infection in human nasal epithelial cells. Overall, our findings suggest that Peli1 contributes to SARS-CoV-2 pathogenesis by promoting virus replication and positively regulating virus-induced inflammatory responses in lung epithelial cells. Peli1 is a therapeutic target to control SARS-CoV-2 -induced disease severity.
{"title":"Pellino-1, a therapeutic target for control of SARS-CoV-2 infection and disease severity","authors":"Binbin Wang , Hongjie Xia , Bi-Hung Peng , Eun-Jin Choi , Bing Tian , Xuping Xie , Shinji Makino , Xiaoyong Bao , Pei-Yong Shi , Vineet Menachery , Tian Wang","doi":"10.1016/j.antiviral.2024.106059","DOIUrl":"10.1016/j.antiviral.2024.106059","url":null,"abstract":"<div><div>Enhanced expression of Pellino-1 (Peli1), a ubiquitin ligase is known to be associated with COVID-19 susceptibility. The underlying mechanisms are not known. Here, we report that mice deficient in Peli1 (<em>Peli1</em><sup><em>−/−</em></sup>) had reduced viral load and attenuated inflammatory immune responses and tissue damage in the lung following SARS-CoV-2 infection. Overexpressing Peli1 in 293 T cells increased SARS-CoV-2 infection via promoting virus replication and transcription, without affecting virus attachment and entry into the cells. Smaducin-6 treatment which is known to disrupt Peli1-mediated NF-KB activation, attenuated inflammatory immune responses in human lung epithelial cells as well as in the lung of K18-hACE2 mice following SARS-CoV-2 infection, though it had minimal effects on SARS-CoV-2 infection in human nasal epithelial cells. Overall, our findings suggest that Peli1 contributes to SARS-CoV-2 pathogenesis by promoting virus replication and positively regulating virus-induced inflammatory responses in lung epithelial cells. Peli1 is a therapeutic target to control SARS-CoV-2 -induced disease severity.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"233 ","pages":"Article 106059"},"PeriodicalIF":4.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845703","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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