Pub Date : 2026-01-20DOI: 10.1016/j.antiviral.2026.106353
Laura Corneillie, Léa Mézière, Claire Montpellier, Benjamin Drouet, Cécile-Marie Aliouat-Denis, Laurence Cocquerel
Hepatitis E virus (HEV) is an emerging zoonotic pathogen and the leading cause of acute viral hepatitis worldwide. Nevertheless, HEV remains largely underestimated and poorly controlled. HEV infects a broad range of host species, transmits through diverse routes and can cause chronic infections in immunocompromised individuals and severe hepatitis in pregnant women. Currently, there is no HEV-specific antiviral treatment available and the only licensed vaccine is restricted to a few countries. Taken together, this highlights its significance as a global health treat and underscores the urgent need for new preventive and therapeutic strategies.
This review provides a comprehensive overview of HEV molecular and cellular biology with a focus on antiviral opportunities. First, we summarize the epidemiology and clinical spectrum of HEV infection, as well as the current prevention, vaccination and treatment strategies. Next, we review the molecular mechanisms underlying HEV entry, replication, and assembly/egress, detailing host and viral factors that represent promising antiviral targets. We present the available in vitro and in vivo experimental models that are essential for studying the HEV life cycle and evaluating therapeutic candidates.
Particular attention is given to recent discoveries in HEV entry pathways, the organization and functions of the ORF1 replicase complex, and host-virus interactions. Importantly, we provide an up-to-date overview of host-targeting antivirals (HTAs) and direct-acting antivirals (DAAs) against HEV that have been identified so far. This review emphasizes how fundamental virology informs drug discovery and paves the way toward the development of effective antivirals against this underestimated pathogen of increasing global concern.
{"title":"Update on the molecular and cellular biology of hepatitis E virus and therapeutic opportunities","authors":"Laura Corneillie, Léa Mézière, Claire Montpellier, Benjamin Drouet, Cécile-Marie Aliouat-Denis, Laurence Cocquerel","doi":"10.1016/j.antiviral.2026.106353","DOIUrl":"10.1016/j.antiviral.2026.106353","url":null,"abstract":"<div><div>Hepatitis E virus (HEV) is an emerging zoonotic pathogen and the leading cause of acute viral hepatitis worldwide. Nevertheless, HEV remains largely underestimated and poorly controlled. HEV infects a broad range of host species, transmits through diverse routes and can cause chronic infections in immunocompromised individuals and severe hepatitis in pregnant women. Currently, there is no HEV-specific antiviral treatment available and the only licensed vaccine is restricted to a few countries. Taken together, this highlights its significance as a global health treat and underscores the urgent need for new preventive and therapeutic strategies.</div><div>This review provides a comprehensive overview of HEV molecular and cellular biology with a focus on antiviral opportunities. First, we summarize the epidemiology and clinical spectrum of HEV infection, as well as the current prevention, vaccination and treatment strategies. Next, we review the molecular mechanisms underlying HEV entry, replication, and assembly/egress, detailing host and viral factors that represent promising antiviral targets. We present the available <em>in vitro</em> and <em>in vivo</em> experimental models that are essential for studying the HEV life cycle and evaluating therapeutic candidates.</div><div>Particular attention is given to recent discoveries in HEV entry pathways, the organization and functions of the ORF1 replicase complex, and host-virus interactions. Importantly, we provide an up-to-date overview of host-targeting antivirals (HTAs) and direct-acting antivirals (DAAs) against HEV that have been identified so far. This review emphasizes how fundamental virology informs drug discovery and paves the way toward the development of effective antivirals against this underestimated pathogen of increasing global concern.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"247 ","pages":"Article 106353"},"PeriodicalIF":4.0,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146028413","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 : 2026-01-19DOI: 10.1016/j.antiviral.2026.106351
Charlotte Hedskog, Lauren Rodriguez, Yu Hu, Jiani Li, Dong Han, Nadine Peinovich, Clarissa Martinez, Pui Yan Ho, Jason K Perry, Juan María González Del Castillo, Yiannis Koullias, Ross Martin, Robert H Hyland
Obeldesivir is an oral nucleoside analog prodrug that targets and inhibits the SARS-CoV-2 RNA-dependent RNA polymerase Nsp12. This study evaluated the development of obeldesivir resistance in participants from the Phase 3, multicenter, double-blind BIRCH study. High-risk, nonhospitalized adults with COVID-19 were randomized to receive obeldesivir or placebo twice daily for 5 days. Mid-turbinate nasal swab samples were collected on Days 1 (baseline), 3, 5, 10, and 15. Amino acid substitutions were identified using deep sequencing and phenotyped using a replicon system. Of the 465 participants randomized and treated, 252 (obeldesivir, 190; placebo, 62) met the sequencing analysis criteria and had sequencing data at baseline. Phenotypic analysis of the 5 Nsp12 substitutions observed at baseline resulted in half-maximal effective concentration (EC50) fold changes ≤1.8 relative to the wildtype reference, indicating no change in susceptibility to obeldesivir. Among participants with baseline and postbaseline sequencing data, 12/73 (16.4 %) and 5/54 (9.3 %) participants in the obeldesivir and placebo groups, respectively, had emergent Nsp12 substitutions. Nine emergent Nsp12 substitutions were detected in the obeldesivir group postbaseline that were not observed in the placebo group. Of these, only 1 substitution (V792I) observed in 1 participant from the obeldesivir group demonstrated a low-level reduction in susceptibility to obeldesivir (EC50 fold change, 4.01). This substitution was first detected on Day 15, and the participant was never hospitalized. The low-to-no change in obeldesivir susceptibility among the treatment-emergent Nsp12 substitutions indicates a high barrier to the development of obeldesivir resistance in high-risk, nonhospitalized patients with COVID-19. Clinicaltrials.gov identifier: NCT05603143.
{"title":"SARS-CoV-2 resistance analyses from the Phase 3 BIRCH study of obeldesivir in high-risk nonhospitalized participants with COVID-19.","authors":"Charlotte Hedskog, Lauren Rodriguez, Yu Hu, Jiani Li, Dong Han, Nadine Peinovich, Clarissa Martinez, Pui Yan Ho, Jason K Perry, Juan María González Del Castillo, Yiannis Koullias, Ross Martin, Robert H Hyland","doi":"10.1016/j.antiviral.2026.106351","DOIUrl":"10.1016/j.antiviral.2026.106351","url":null,"abstract":"<p><p>Obeldesivir is an oral nucleoside analog prodrug that targets and inhibits the SARS-CoV-2 RNA-dependent RNA polymerase Nsp12. This study evaluated the development of obeldesivir resistance in participants from the Phase 3, multicenter, double-blind BIRCH study. High-risk, nonhospitalized adults with COVID-19 were randomized to receive obeldesivir or placebo twice daily for 5 days. Mid-turbinate nasal swab samples were collected on Days 1 (baseline), 3, 5, 10, and 15. Amino acid substitutions were identified using deep sequencing and phenotyped using a replicon system. Of the 465 participants randomized and treated, 252 (obeldesivir, 190; placebo, 62) met the sequencing analysis criteria and had sequencing data at baseline. Phenotypic analysis of the 5 Nsp12 substitutions observed at baseline resulted in half-maximal effective concentration (EC<sub>50</sub>) fold changes ≤1.8 relative to the wildtype reference, indicating no change in susceptibility to obeldesivir. Among participants with baseline and postbaseline sequencing data, 12/73 (16.4 %) and 5/54 (9.3 %) participants in the obeldesivir and placebo groups, respectively, had emergent Nsp12 substitutions. Nine emergent Nsp12 substitutions were detected in the obeldesivir group postbaseline that were not observed in the placebo group. Of these, only 1 substitution (V792I) observed in 1 participant from the obeldesivir group demonstrated a low-level reduction in susceptibility to obeldesivir (EC<sub>50</sub> fold change, 4.01). This substitution was first detected on Day 15, and the participant was never hospitalized. The low-to-no change in obeldesivir susceptibility among the treatment-emergent Nsp12 substitutions indicates a high barrier to the development of obeldesivir resistance in high-risk, nonhospitalized patients with COVID-19. Clinicaltrials.gov identifier: NCT05603143.</p>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":" ","pages":"106351"},"PeriodicalIF":4.0,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146017287","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}
Influenza is a major global threat due to several factors, including great zoonotic potential, ongoing antigenic drift, limited effectiveness of current vaccines, and the emergence of drug-resistant viral strains. Broad-spectrum therapeutic regimens that can treat vulnerable populations, enable faster resolution of symptoms, and decrease fatality rates are a long-sought objective for influenza. Here, we report the development of NanoSTING, a liposomally encapsulated STING agonist (cGAMP), as a single-dose intranasal treatment of influenza. We demonstrate that NanoSTING is stable under simple refrigeration conditions, with no loss of encapsulated cGAMP, for up to a year. A single dose of NanoSTING administered intranasally induced robust type I interferon responses in the nasal and lung tissue of mice without observable toxicity. In mouse challenge models of influenza A (H1N1 or highly pathogenic H5N1) and influenza B, NanoSTING provided therapeutic protection at least as effective as ten doses of oseltamivir. NanoSTING demonstrated therapeutic efficacy even when administered 48–72 h post-infection. Furthermore, NanoSTING maintained its activity in aged and immunocompromised mice, as evidenced by the robust induction of interferon responses in nasal tissues, highlighting its potential for use in vulnerable individuals. These attributes of NanoSTING support its potential use as a promising host-directed anti-viral with a large therapeutic window and broad-spectrum efficacy.
{"title":"Therapeutic intranasal delivery of NanoSTING provides broad protection against seasonal and highly pathogenic influenza strains","authors":"Ankita Leekha , Kate Reichel , Brett Hurst , Navin Varadarajan","doi":"10.1016/j.antiviral.2026.106342","DOIUrl":"10.1016/j.antiviral.2026.106342","url":null,"abstract":"<div><div>Influenza is a major global threat due to several factors, including great zoonotic potential, ongoing antigenic drift, limited effectiveness of current vaccines, and the emergence of drug-resistant viral strains. Broad-spectrum therapeutic regimens that can treat vulnerable populations, enable faster resolution of symptoms, and decrease fatality rates are a long-sought objective for influenza. Here, we report the development of NanoSTING, a liposomally encapsulated STING agonist (cGAMP), as a single-dose intranasal treatment of influenza. We demonstrate that NanoSTING is stable under simple refrigeration conditions, with no loss of encapsulated cGAMP, for up to a year. A single dose of NanoSTING administered intranasally induced robust type I interferon responses in the nasal and lung tissue of mice without observable toxicity. In mouse challenge models of influenza A (H1N1 or highly pathogenic H5N1) and influenza B, NanoSTING provided therapeutic protection at least as effective as ten doses of oseltamivir. NanoSTING demonstrated therapeutic efficacy even when administered 48–72 h post-infection. Furthermore, NanoSTING maintained its activity in aged and immunocompromised mice, as evidenced by the robust induction of interferon responses in nasal tissues, highlighting its potential for use in vulnerable individuals. These attributes of NanoSTING support its potential use as a promising host-directed anti-viral with a large therapeutic window and broad-spectrum efficacy.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"247 ","pages":"Article 106342"},"PeriodicalIF":4.0,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987548","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 : 2026-01-14DOI: 10.1016/j.antiviral.2026.106344
Yunzhe Kang , Rui Wang , Lulu Yao , Xiuwen Yang , Wenhui Zhu , Lele Wang , Gaiping Zhang , Guoqing Zhuang , Aijun Sun
Marek's disease virus (MDV) is an oncogenic alphaherpesvirus causing rapid onset of malignant T-cell lymphomas in chickens. UL23-encoded thymidine kinase (TK) has highly conserved sequences in distinctive alphaherpesviruses. However, its enzymatic activity in viral replication and pathogenesis is poorly understood. Here, we found that the nucleotide-binding sites and the functional domains related to activity of TK from different alphaherpesviruses are strongly conserved. We show that an MDV-1 UL23-null mutation (Md5BACΔUL23) significantly reduces MDV replication in vitro and in vivo. Interestingly, chimeric viruses with replacement of MDV-1 UL23 with MDV-2, HVT, PRV, or HSV-1 UL23 showed partial recovery of MDV replication and pathogenicity. In addition, Md5BACΔUL23 infection resulted in higher survival rate and lower MDV-specific tumor incidence, which could be partially compensated by chimeric viruses. The replication properties of UL23 chimeric alphaherpesviruses are susceptible to acyclovir inhibition, whereas Md5BACΔUL23 exhibits complete resistance. Overall, our establishment of the MDV-TK chimeric model provides a robust basis for evaluating TK-targeted therapeutics, accelerating clinical translation of novel anti-herpesvirus strategies.
{"title":"The UL23 thymidine kinase of Marek's disease virus is a target for anti-HSV drug development","authors":"Yunzhe Kang , Rui Wang , Lulu Yao , Xiuwen Yang , Wenhui Zhu , Lele Wang , Gaiping Zhang , Guoqing Zhuang , Aijun Sun","doi":"10.1016/j.antiviral.2026.106344","DOIUrl":"10.1016/j.antiviral.2026.106344","url":null,"abstract":"<div><div>Marek's disease virus (MDV) is an oncogenic alphaherpesvirus causing rapid onset of malignant T-cell lymphomas in chickens. <em>UL23</em>-encoded thymidine kinase (TK) has highly conserved sequences in distinctive alphaherpesviruses. However, its enzymatic activity in viral replication and pathogenesis is poorly understood. Here, we found that the nucleotide-binding sites and the functional domains related to activity of TK from different alphaherpesviruses are strongly conserved. We show that an MDV-1 <em>UL23</em>-null mutation (Md5BACΔ<em>UL23</em>) significantly reduces MDV replication <em>in vitro</em> and <em>in vivo</em>. Interestingly, chimeric viruses with replacement of MDV-1 <em>UL23</em> with MDV-2, HVT, PRV, or HSV-1 <em>UL23</em> showed partial recovery of MDV replication and pathogenicity. In addition, Md5BACΔ<em>UL23</em> infection resulted in higher survival rate and lower MDV-specific tumor incidence, which could be partially compensated by chimeric viruses. The replication properties of <em>UL23</em> chimeric alphaherpesviruses are susceptible to acyclovir inhibition, whereas Md5BACΔ<em>UL23</em> exhibits complete resistance. Overall, our establishment of the MDV-TK chimeric model provides a robust basis for evaluating TK-targeted therapeutics, accelerating clinical translation of novel anti-herpesvirus strategies.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"247 ","pages":"Article 106344"},"PeriodicalIF":4.0,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987929","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 : 2026-01-08DOI: 10.1016/j.antiviral.2026.106343
Yasuteru Sakurai , Minato Hirano , Sayaka Okada , Yohei Kurosaki , Rokusuke Yoshikawa , John N. Barr , Roger Hewson , Kentaro Yoshii , Jiro Yasuda
Crimean–Congo hemorrhagic fever virus (CCHFV) is a tick-borne enveloped virus that causes a severe disease in humans. Despite its wide geographic distribution, no approved vaccines or therapeutics exist. In this study, we achieved high-titer production of pseudotyped virus bearing CCHFV glycoproteins with a C-terminal truncation. Screening over 3,600 small compounds using this pseudotyped virus identified claramine and anidulafungin as CCHFV entry inhibitors. These hit compounds, as well as caspofungin, which is related to anidulafungin, inhibited pseudotyped viral infection in human liver cells and vascular endothelial cells. They inhibited infection of pseudotyped virus with glycoproteins from various CCHFV strains and Hazara virus, a nairovirus closely related to CCHFV. Using a quantitative fusion assay, the identified inhibitors were shown to block membrane fusion via CCHFV glycoproteins. Moreover, they inhibited infection of replication-competent Hazara virus. Therefore, the assays developed in this study were successful in identifying CCHFV entry inhibitors that target membrane fusion.
{"title":"Identification of claramine and anidulafungin as entry inhibitors of Crimean–Congo hemorrhagic fever virus","authors":"Yasuteru Sakurai , Minato Hirano , Sayaka Okada , Yohei Kurosaki , Rokusuke Yoshikawa , John N. Barr , Roger Hewson , Kentaro Yoshii , Jiro Yasuda","doi":"10.1016/j.antiviral.2026.106343","DOIUrl":"10.1016/j.antiviral.2026.106343","url":null,"abstract":"<div><div>Crimean–Congo hemorrhagic fever virus (CCHFV) is a tick-borne enveloped virus that causes a severe disease in humans. Despite its wide geographic distribution, no approved vaccines or therapeutics exist. In this study, we achieved high-titer production of pseudotyped virus bearing CCHFV glycoproteins with a C-terminal truncation. Screening over 3,600 small compounds using this pseudotyped virus identified claramine and anidulafungin as CCHFV entry inhibitors. These hit compounds, as well as caspofungin, which is related to anidulafungin, inhibited pseudotyped viral infection in human liver cells and vascular endothelial cells. They inhibited infection of pseudotyped virus with glycoproteins from various CCHFV strains and Hazara virus, a nairovirus closely related to CCHFV. Using a quantitative fusion assay, the identified inhibitors were shown to block membrane fusion via CCHFV glycoproteins. Moreover, they inhibited infection of replication-competent Hazara virus. Therefore, the assays developed in this study were successful in identifying CCHFV entry inhibitors that target membrane fusion.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"246 ","pages":"Article 106343"},"PeriodicalIF":4.0,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145922336","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 : 2026-01-02DOI: 10.1016/j.antiviral.2025.106341
Chang Wang , Huoyan Tong , Xi Zhou , Yuan Fang
Enteroviruses (EVs) are significant human pathogens, and the development of orally available, broad-spectrum antiviral agents remains an urgent need. The viral protein 2C, a conserved nonstructural protein with helicase activity, is a promising target for antiviral intervention. Although the peptide 2CL was previously identified as a 2C inhibitor, its cell-penetrating peptide motif and extended core sequence may limit its binding efficiency and pharmacological properties. Here, we report the optimization of 2CL to develop a novel peptidomimetic, 2CA-1, with a more compact structure and absence of a cell-penetrating motif. Besides its potent cellular antiviral activity, achieved by precise docking into the 2C binding pocket to inhibit helicase function, 2CA-1 exhibited excellent oral bioavailability in a murine model, significantly reducing viral loads and showing broad efficacy against multiple enteroviruses including CV-A6, CV-A16, CV-B3, Echo11, EV-D68 and rhinovirus. This study not only presents 2CA-1 as an optimized 2C-targeted antiviral candidate but also highlights its potential as an orally available and broad-spectrum therapeutic against EVs.
{"title":"An orally available peptidomimetic with broad-spectrum antiviral activity targeting the enterovirus 2C helicase","authors":"Chang Wang , Huoyan Tong , Xi Zhou , Yuan Fang","doi":"10.1016/j.antiviral.2025.106341","DOIUrl":"10.1016/j.antiviral.2025.106341","url":null,"abstract":"<div><div>Enteroviruses (EVs) are significant human pathogens, and the development of orally available, broad-spectrum antiviral agents remains an urgent need. The viral protein 2C, a conserved nonstructural protein with helicase activity, is a promising target for antiviral intervention. Although the peptide 2CL was previously identified as a 2C inhibitor, its cell-penetrating peptide motif and extended core sequence may limit its binding efficiency and pharmacological properties. Here, we report the optimization of 2CL to develop a novel peptidomimetic, 2CA-1, with a more compact structure and absence of a cell-penetrating motif. Besides its potent cellular antiviral activity, achieved by precise docking into the 2C binding pocket to inhibit helicase function, 2CA-1 exhibited excellent oral bioavailability in a murine model, significantly reducing viral loads and showing broad efficacy against multiple enteroviruses including CV-A6, CV-A16, CV-B3, Echo11, EV-D68 and rhinovirus. This study not only presents 2CA-1 as an optimized 2C-targeted antiviral candidate but also highlights its potential as an orally available and broad-spectrum therapeutic against EVs.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"246 ","pages":"Article 106341"},"PeriodicalIF":4.0,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145881762","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 : 2025-12-31DOI: 10.1016/j.antiviral.2025.106340
Sunwen Chou , Alexis Minyard , Justin Watanabe
In two recent Phase 3 clinical trials of maribavir that also involved existing standard therapies, many uncharacterized cytomegalovirus UL54 DNA polymerase genetic variants were encountered. Six UL54 mutations were selected for phenotyping, based on proximity to published resistance loci and quality of sequencing information. UL54 amino acid substitutions E949K and E949Q conferred foscarnet resistance with slightly decreased ganciclovir and cidofovir susceptibility, representing a novel palm domain resistance locus. UL54 N498S and P598S mutants had slight decreases in ganciclovir and cidofovir susceptibility, with N498S also having a slightly decreased foscarnet susceptibility. No drug resistance was attributed to A786V and A928V. Retesting published phenotypes for UL54 mutants D515E, D542E, A543V and A928T revealed some discordant findings, including ganciclovir resistance for D542E and A543V, and no drug resistance for D515E and A928T. These genotype-phenotype correlations add to the evidence base for clinical diagnostic testing of cytomegalovirus drug resistance.
{"title":"A new locus of foscarnet resistance in the cytomegalovirus UL54 DNA polymerase gene among uncharacterized mutations in recent clinical trials","authors":"Sunwen Chou , Alexis Minyard , Justin Watanabe","doi":"10.1016/j.antiviral.2025.106340","DOIUrl":"10.1016/j.antiviral.2025.106340","url":null,"abstract":"<div><div>In two recent Phase 3 clinical trials of maribavir that also involved existing standard therapies, many uncharacterized cytomegalovirus UL54 DNA polymerase genetic variants were encountered. Six UL54 mutations were selected for phenotyping, based on proximity to published resistance loci and quality of sequencing information. UL54 amino acid substitutions E949K and E949Q conferred foscarnet resistance with slightly decreased ganciclovir and cidofovir susceptibility, representing a novel palm domain resistance locus. UL54 N498S and P598S mutants had slight decreases in ganciclovir and cidofovir susceptibility, with N498S also having a slightly decreased foscarnet susceptibility. No drug resistance was attributed to A786V and A928V. Retesting published phenotypes for UL54 mutants D515E, D542E, A543V and A928T revealed some discordant findings, including ganciclovir resistance for D542E and A543V, and no drug resistance for D515E and A928T. These genotype-phenotype correlations add to the evidence base for clinical diagnostic testing of cytomegalovirus drug resistance.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"246 ","pages":"Article 106340"},"PeriodicalIF":4.0,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145891928","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 : 2025-12-29DOI: 10.1016/j.antiviral.2025.106339
Lauren Rodriguez, Yu Hu, Jiani Li, Dong Han, Nadine Peinovich, Clarissa Martinez, Pui Yan Ho, Jason K Perry, Ross Martin, Onyema Ogbuagu, Amos Lichtman, Robert H Hyland, Charlotte Hedskog
Obeldesivir is an oral nucleoside analog prodrug inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase Nsp12. This study evaluated baseline and treatment-emergent viral resistance to obeldesivir in participants from OAKTREE, a multicenter, double-blind trial wherein nonhospitalized adolescents and adults with COVID-19 at low risk of developing severe disease were randomized 1:1 to receive obeldesivir or placebo twice daily for 5 days. Deep sequencing was performed on mid-turbinate nasal swab samples collected on Days 1 (baseline), 3, 5, 10, 15, 20, and 29 from participants who met sequencing analysis criteria. Amino acid substitutions detected in the SARS-CoV-2 replication complex components were phenotyped in a replicon system. Overall, 1425 participants (obeldesivir, 725; placebo, 700) met sequencing analysis criteria and had baseline sequencing data. Thirty-five baseline Nsp12 substitutions, including P323L and G671S, were observed in ≥3 participants. Phenotyping of baseline Nsp12 substitutions showed obeldesivir half-maximal effective concentration (EC50) fold changes relative to wildtype that were within assay variability (≤2.15-fold). Among participants with baseline and postbaseline sequencing data, the proportion of emergent Nsp12 substitutions was similar between groups (obeldesivir, 35/208 [16.8 %]; placebo, 23/120 [19.2 %]). Twenty-five emergent Nsp12 substitutions were detected in the obeldesivir group but not in the placebo group. Only 1 emergent Nsp12 substitution (C799F) from 1 participant in the obeldesivir group was associated with reduced obeldesivir susceptibility, with a 3.35-fold change in EC50 versus wildtype. The low-to-no change in obeldesivir susceptibility among treatment-emergent Nsp12 substitutions indicated a high barrier to development of obeldesivir resistance in low-risk, nonhospitalized patients with COVID-19. ClinicalTrials.gov identifier: NCT05715528.
{"title":"SARS-CoV-2 resistance analyses from the Phase 3 OAKTREE study of obeldesivir in low-risk nonhospitalized participants with COVID-19.","authors":"Lauren Rodriguez, Yu Hu, Jiani Li, Dong Han, Nadine Peinovich, Clarissa Martinez, Pui Yan Ho, Jason K Perry, Ross Martin, Onyema Ogbuagu, Amos Lichtman, Robert H Hyland, Charlotte Hedskog","doi":"10.1016/j.antiviral.2025.106339","DOIUrl":"10.1016/j.antiviral.2025.106339","url":null,"abstract":"<p><p>Obeldesivir is an oral nucleoside analog prodrug inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase Nsp12. This study evaluated baseline and treatment-emergent viral resistance to obeldesivir in participants from OAKTREE, a multicenter, double-blind trial wherein nonhospitalized adolescents and adults with COVID-19 at low risk of developing severe disease were randomized 1:1 to receive obeldesivir or placebo twice daily for 5 days. Deep sequencing was performed on mid-turbinate nasal swab samples collected on Days 1 (baseline), 3, 5, 10, 15, 20, and 29 from participants who met sequencing analysis criteria. Amino acid substitutions detected in the SARS-CoV-2 replication complex components were phenotyped in a replicon system. Overall, 1425 participants (obeldesivir, 725; placebo, 700) met sequencing analysis criteria and had baseline sequencing data. Thirty-five baseline Nsp12 substitutions, including P323L and G671S, were observed in ≥3 participants. Phenotyping of baseline Nsp12 substitutions showed obeldesivir half-maximal effective concentration (EC<sub>50</sub>) fold changes relative to wildtype that were within assay variability (≤2.15-fold). Among participants with baseline and postbaseline sequencing data, the proportion of emergent Nsp12 substitutions was similar between groups (obeldesivir, 35/208 [16.8 %]; placebo, 23/120 [19.2 %]). Twenty-five emergent Nsp12 substitutions were detected in the obeldesivir group but not in the placebo group. Only 1 emergent Nsp12 substitution (C799F) from 1 participant in the obeldesivir group was associated with reduced obeldesivir susceptibility, with a 3.35-fold change in EC<sub>50</sub> versus wildtype. The low-to-no change in obeldesivir susceptibility among treatment-emergent Nsp12 substitutions indicated a high barrier to development of obeldesivir resistance in low-risk, nonhospitalized patients with COVID-19. ClinicalTrials.gov identifier: NCT05715528.</p>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":" ","pages":"106339"},"PeriodicalIF":4.0,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145877575","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}
Re-emerging arthropod-borne viruses such as Mayaro (MAYV), Chikungunya (CHIKV), and Zika (ZIKV) pose a growing global health concern as Aedes mosquito populations expand. These arboviruses infect innate immune cells, particularly monocyte-derived macrophages (MDMs), which support viral replication and serve as reservoirs that facilitate dissemination. Because no effective antiviral treatments are available, strategies that modulate macrophage responses and restrict viral replication are urgently needed. Here, we evaluated the immunomodulatory and antiviral effects of 2-deoxy-D-glucose (2-DG) in human MDMs. First, we assessed how 2-DG shapes transcriptional responses to lipopolysaccharide (LPS), a canonical TLR4 agonist. Co-treatment with 2-DG and LPS induced genes linked to inflammatory, antiviral, and endoplasmic reticulum (ER) stress pathways. Notably, IL10 mRNA and IL-10 protein displayed an inverse relationship with metabolic stress yet correlated positively with inflammatory and antiviral gene expression, whereas GADD34 was positively associated with both inflammatory and ER stress responses, suggesting an integrative regulatory role. We next investigated whether 2-DG pretreatment limits replication of MAYV, CHIKV, and ZIKV in infected MDMs. Antiviral assays demonstrated that 2-DG reduced replication of all three arboviruses by approximately one log10. Additional analyses revealed distinct temporal sensitivities: MAYV and CHIKV showed early and late susceptibility, whereas ZIKV exhibited a distinct kinetic profile. Mechanistic experiments confirmed that 2-DG acts post-entry primarily and reverses the antiviral phenotype observed in LPS-primed MDMs. Collectively, these findings reveal crosstalk among inflammatory, antiviral, and ER stress pathways and demonstrate that 2-DG modulates LPS-driven inflammation while reducing replication of pathogenic arboviruses in human MDMs.
{"title":"2-Deoxy-D-glucose attenuates lipopolysaccharide-induced inflammation and restricts Zika, Chikungunya, and Mayaro virus replication in monocyte-derived macrophages","authors":"Y.S. Tamayo-Molina, Yisel García-Marin, Silvio Urcuqui-Inchima","doi":"10.1016/j.antiviral.2025.106338","DOIUrl":"10.1016/j.antiviral.2025.106338","url":null,"abstract":"<div><div>Re-emerging arthropod-borne viruses such as Mayaro (MAYV), Chikungunya (CHIKV), and Zika (ZIKV) pose a growing global health concern as <em>Aedes</em> mosquito populations expand. These arboviruses infect innate immune cells, particularly monocyte-derived macrophages (MDMs), which support viral replication and serve as reservoirs that facilitate dissemination. Because no effective antiviral treatments are available, strategies that modulate macrophage responses and restrict viral replication are urgently needed. Here, we evaluated the immunomodulatory and antiviral effects of 2-deoxy-D-glucose (2-DG) in human MDMs. First, we assessed how 2-DG shapes transcriptional responses to lipopolysaccharide (LPS), a canonical TLR4 agonist. Co-treatment with 2-DG and LPS induced genes linked to inflammatory, antiviral, and endoplasmic reticulum (ER) stress pathways. Notably, IL10 mRNA and IL-10 protein displayed an inverse relationship with metabolic stress yet correlated positively with inflammatory and antiviral gene expression, whereas GADD34 was positively associated with both inflammatory and ER stress responses, suggesting an integrative regulatory role. We next investigated whether 2-DG pretreatment limits replication of MAYV, CHIKV, and ZIKV in infected MDMs. Antiviral assays demonstrated that 2-DG reduced replication of all three arboviruses by approximately one log<sub>10</sub>. Additional analyses revealed distinct temporal sensitivities: MAYV and CHIKV showed early and late susceptibility, whereas ZIKV exhibited a distinct kinetic profile. Mechanistic experiments confirmed that 2-DG acts post-entry primarily and reverses the antiviral phenotype observed in LPS-primed MDMs. Collectively, these findings reveal crosstalk among inflammatory, antiviral, and ER stress pathways and demonstrate that 2-DG modulates LPS-driven inflammation while reducing replication of pathogenic arboviruses in human MDMs.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"246 ","pages":"Article 106338"},"PeriodicalIF":4.0,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145838909","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 : 2025-12-22DOI: 10.1016/j.antiviral.2025.106337
Stephen R. Welch , Jessica R. Spengler , Sarah C. Genzer , Jessica R. Harmon , JoAnn D. Coleman-McCray , Teresa E. Sorvillo , Stuart T. Nichol , Christina F. Spiropoulou
Defective interfering particles (DIPs) are naturally occurring virus-like particles containing truncated fragments of the parental viral genome and have gained interest as potential medical countermeasures (MCMs) against viral infections. Using the Syrian hamster model of Nipah virus (NiV) disease, we previously showed that treatment with artificially produced NiV-derived DIPs markedly reduced clinical signs and mortality. However, DIP production required infectious NiV and BSL-4 containment, creating a major barrier to clinical translation. Here, we describe an improved, non-infectious, BSL-2-compatible NiV replicon system for DIP generation that eliminates the need for infectious virus. DIPs produced using this system inhibited virus in vitro and retained full protective efficacy in hamsters. By removing the requirement for high-containment virus, this approach overcomes key regulatory and practical hurdles, enabling advancement of DIP-based therapeutics toward clinical evaluation and eventual use against NiV and related henipaviruses.
{"title":"Nipah virus-derived defective interfering particles generated using non-infectious viral replicon particles confer protective efficacy comparable to those produced with standard full-length infectious virus","authors":"Stephen R. Welch , Jessica R. Spengler , Sarah C. Genzer , Jessica R. Harmon , JoAnn D. Coleman-McCray , Teresa E. Sorvillo , Stuart T. Nichol , Christina F. Spiropoulou","doi":"10.1016/j.antiviral.2025.106337","DOIUrl":"10.1016/j.antiviral.2025.106337","url":null,"abstract":"<div><div>Defective interfering particles (DIPs) are naturally occurring virus-like particles containing truncated fragments of the parental viral genome and have gained interest as potential medical countermeasures (MCMs) against viral infections. Using the Syrian hamster model of Nipah virus (NiV) disease, we previously showed that treatment with artificially produced NiV-derived DIPs markedly reduced clinical signs and mortality. However, DIP production required infectious NiV and BSL-4 containment, creating a major barrier to clinical translation. Here, we describe an improved, non-infectious, BSL-2-compatible NiV replicon system for DIP generation that eliminates the need for infectious virus. DIPs produced using this system inhibited virus <em>in vitro</em> and retained full protective efficacy in hamsters. By removing the requirement for high-containment virus, this approach overcomes key regulatory and practical hurdles, enabling advancement of DIP-based therapeutics toward clinical evaluation and eventual use against NiV and related henipaviruses.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"246 ","pages":"Article 106337"},"PeriodicalIF":4.0,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145826728","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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