Antiviral research最新文献

{"title":"Pretreatment viral quasispecies characteristics and evolutionary phases correlate with HBsAg seroconversion in peginterferon-alfa-2a-treated children with HBeAg-positive chronic hepatitis B","authors":"Juncheng Yang ,&nbsp;Guifeng Yang ,&nbsp;Haitang He ,&nbsp;Hai Liu ,&nbsp;Qunfang Fu ,&nbsp;Xiaoting Wu ,&nbsp;Ran Meng ,&nbsp;Zhuoyue Li ,&nbsp;Qian Zhao ,&nbsp;Kangxian Luo ,&nbsp;Zhihua Liu","doi":"10.1016/j.antiviral.2025.106291","DOIUrl":"10.1016/j.antiviral.2025.106291","url":null,"abstract":"<div><h3>Background &amp; aims</h3><div>To evaluate baseline HBV quasispecies (QS) characteristics as a predictor of HBsAg seroconversion in peginterferon-alfa-2a-treated HBeAg-positive pediatric chronic hepatitis B (CHB).</div></div><div><h3>Methods</h3><div>25 patients achieved HBsAg seroconversion (SS group) and another 25 did not (SN group) were enrolled, matched for baseline profiles. Full-length HBV genomes were obtained from pretreatment serum via clone sequencing. Twelve untreated carriers (CA group) served as controls.</div></div><div><h3>Results</h3><div>SN group demonstrated significantly higher genetic distance (GD) and mutation frequency index (MFI) in the preCore/Core (preC/C) gene versus SS and CA groups (p &lt; 0.05). Treatment failure exclusively correlated with G1896A/C1913A/C2078G mutations. Jonckheere-Terpstra test confirmed a CA→SS→SN diversity gradient in preC/C (p &lt; 0.05). Non-invasive fibrosis indices increased across CA→SS→SN (p &lt; 0.05) and correlated positively with QS diversity. Evolutionary analyses revealed divergent haplotype clustering in SN versus star-like radiation patterns in CA/SS. Phylogenetic analysis positioned CA/SS haplotypes at earlier evolutionary phases, while SN haplotypes at a later phase. Notably, haplotypes harboring the three aforementioned mutations were also located at the later phase. Positive selection analysis identified two SN-specific mutations (codon 34[C1913A] and 89[C2078G]). A LASSO-derived predictive model (age, C1913A/C2078G, preC/C MFI) yielded the area under the receiver operating characteristic curve (AUROC) 0.814 (sensitivity 92 %, specificity 68 %).</div></div><div><h3>Conclusions</h3><div>Lower baseline HBV quasispecies diversity predicts Peginterferon-alfa-2a-induced HBsAg seroconversion in pediatric CHB. The observed diversity continuum, association with fibrosis indices, suggests seroconversion occurs preferentially during earlier hepatitis phases. Pretreatment viral genetic profiling may optimize therapeutic timing, highlighting its prognostic value for childhood HBV management.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"244 ","pages":"Article 106291"},"PeriodicalIF":4.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145290807","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}

{"title":"SUCLG2 plays a crucial role in the activity of Nitazoxanide against Japanese encephalitis virus","authors":"Min Wei ,&nbsp;Rumeng Ma ,&nbsp;Xiaoyang Wang ,&nbsp;Chunmei Wang ,&nbsp;Mi Wang ,&nbsp;Han Bai ,&nbsp;Wenchong Ye ,&nbsp;Wen Zhou ,&nbsp;Keyu Zhang","doi":"10.1016/j.antiviral.2025.106301","DOIUrl":"10.1016/j.antiviral.2025.106301","url":null,"abstract":"<div><div>Japanese encephalitis virus (JEV) is the primary causative agent of viral encephalitis, and Nitazoxanide (NTZ) has been shown to exhibit potent antiviral activity against JEV both in vitro and in vivo. Previous studies have demonstrated that NTZ modulates the expression of succinyl-CoA synthetase GDP forming subunit β (SUCLG2), a GTP-specific succinyl-CoA synthetase, in JEV-infected cells. However, the functional role and underlying mechanism of SUCLG2 in NTZ-mediated antiviral effects against JEV remain poorly understood. In this study, we found that SiRNA-mediated knockdown of SUCLG2 significantly enhanced JEV proliferation in BHK-21 cells, whereas overexpression of SUCLG2 markedly suppressed viral replication. Moreover, SUCLG2 overexpression attenuated ROS production induced by JEV infection and promoted ATP recovery. Furthermore, SUCLG2 activated innate immunity by enhancing IFN-β expression. Additionally, our findings indicate that SUCLG2 exhibits relatively weak direct binding affinity with NTZ. In conclusion, our results demonstrate that SUCLG2 plays a critical role in mediating the antiviral activity of NTZ against JEV, providing novel insights into the molecular mechanisms underlying NTZ's antiviral efficacy.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"244 ","pages":"Article 106301"},"PeriodicalIF":4.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145413769","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}

{"title":"Deciphering letermovir's mode of action and resistance mutation effects","authors":"C. Gourin ,&nbsp;T. Flores ,&nbsp;C. Lefèvre ,&nbsp;S. Alain ,&nbsp;G. Ligat ,&nbsp;S. Hantz","doi":"10.1016/j.antiviral.2025.106289","DOIUrl":"10.1016/j.antiviral.2025.106289","url":null,"abstract":"<div><div>Human cytomegalovirus is an opportunistic pathogen responsible for severe infections in immunocompromised patients, the leading cause of congenital infections worldwide, and potentially implicated in carcinogenesis. The HCMV terminase complex (pUL56-pUL89-pUL51) has emerged as a key target for antiviral drug development. Letermovir, an antiviral agent targeting this complex, inhibits viral DNA packaging, but resistance-associated mutations have already been identified within subunits. Moreover, the precise mechanism of action of letermovir remains incompletely understood.</div><div>We investigated interactions among terminase subunits in presence or absence of letermovir. Wild-type and mutant forms of these proteins (including resistance mutations V236M, L241P, L257I, C325Y, R369M in pUL56 and A95V in pUL51) were cloned into NanoBiT® PPI and pCI-neo vectors. Letermovir was added after transfection in HEK293T cells, and protein-protein interactions were assessed.</div><div>Our results show letermovir does not disrupt interactions between wild-type terminase subunits. Resistance-associated mutations modulate the strength of these interactions, with certain mutations (such as pUL56 V236M and L257I) significantly enhancing or reducing binding. Notably, double mutants exhibited synergistic effects. Structural analysis using the AlphaFold3 platform revealed differences between the mutation site of pUL56 and its HSV-1 counterpart pUL28. A hypothetical 3D analysis based on the cryo-EM structure of the HSV-1 terminase complex showed that resistance mutations were oriented outside the complex.</div><div>These findings suggest letermovir does not act by directly inhibiting interactions among HCMV terminase subunits. Analysis of resistance-associated mutations provides insight into the molecular basis of HCMV resistance to letermovir and may inform development of novel antiviral strategies targeting the terminase complex.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"244 ","pages":"Article 106289"},"PeriodicalIF":4.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145257234","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}

{"title":"Antiviral susceptibility monitoring: testing algorithm, methods, and findings for influenza season, 2023–2024","authors":"Mira C. Patel ,&nbsp;Ha T. Nguyen ,&nbsp;Vasiliy P. Mishin ,&nbsp;Philippe Noriel Q. Pascua ,&nbsp;Chloe Champion ,&nbsp;Mercedes Lopez-Esteva ,&nbsp;Angiezel Merced-Morales ,&nbsp;Alicia Budd ,&nbsp;Marie K. Kirby ,&nbsp;Benjamin Rambo-Martin ,&nbsp;Jennifer Laplante ,&nbsp;Allen Bateman ,&nbsp;Kirsten St. George ,&nbsp;Maureen Sullivan ,&nbsp;John Steel ,&nbsp;Rebecca J. Kondor ,&nbsp;Larisa V. Gubareva","doi":"10.1016/j.antiviral.2025.106299","DOIUrl":"10.1016/j.antiviral.2025.106299","url":null,"abstract":"<div><div>Antiviral susceptibility monitoring is integral to influenza surveillance conducted by CDC in collaboration with partners. Here, we outlined the algorithm and methods used for assessing antiviral susceptibility of viruses collected during 2023–2024 season. Virus specimens were provided by public health laboratories in the United States (US) and by laboratories in other countries that belong to the Pan American Health Organization. In the US, antiviral susceptibility surveillance conducted nationally is strengthened by sequence-only analysis of additional viruses collected at a state level. Viral genome sequence analysis was the primary approach to assess susceptibility to M2 blockers (n = 5123), neuraminidase (NA) inhibitors (n = 6874), and a polymerase acidic protein (PA) inhibitor (baloxavir, n = 6567). Over 99 % of type A viruses had M2-S31N that confers resistance to M2 blockers. Although oseltamivir-resistant viruses carrying NA-H275Y (N1 numbering) were rare (0.35 %), a cluster of four such viruses was identified in Haiti. Viruses with other NA mutations conferring reduced inhibition by NA inhibitor(s) were also detected sporadically. This includes a cluster of three influenza B viruses in Texas that shared a new mutation, NA-A245G conferring reduced inhibition by peramivir. Three viruses with reduced baloxavir susceptibility were identified, which had PA-I38T, PA-Y24C or PA-V122A; the latter two new mutations identified through augmented approach to sequence analysis. To monitor baseline susceptibility, supplementary <em>in vitro</em> testing was conducted on approximately 7 % of viruses using NA inhibition assay and cell culture-based assay IRINA. Implementation of Sequence First approach provided comprehensive and high throughput methodology for antiviral susceptibility assessment and reduced redundant phenotypic testing.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"244 ","pages":"Article 106299"},"PeriodicalIF":4.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285446","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}

{"title":"Design, synthesis and biological evaluation of a novel series of conjugates of N1-(phosphonoalkyl)-1,2,3-triazoles and N3-benzyl-6-bromoquinazoline-2,4-diones with anti-RSV activity","authors":"Iwona E. Głowacka ,&nbsp;Mirthe Graus ,&nbsp;Dorota G. Piotrowska ,&nbsp;Kurt Vermeire","doi":"10.1016/j.antiviral.2025.106303","DOIUrl":"10.1016/j.antiviral.2025.106303","url":null,"abstract":"<div><div>Respiratory syncytial virus (RSV) is a major cause of acute lower respiratory infections and hospitalization in young children, but also poses a significant threat to elderly, high-risk adults, and immuno-compromised patients. Despite major progress regarding vaccines and RSV prophylaxis, the current arsenal of RSV antivirals is very limited. A new series of conjugates of N1-(phosphonoalkyl)-1,2,3-triazoles and 6-bromoquinazoline-2,4-diones functionalized with the 2-, 3- and 4-nitrobenzyl, 3-fluorobenzyl or 3<em>-</em>chlorobenzyl at N3 position of quinazoline-2,4-dione moiety were synthesized and evaluated for their potential antiviral activity. Among all tested compounds, conjugates <strong>1 cb</strong> and <strong>1 fb</strong> showed the strongest anti-RSV activity (high nanomolar to low micromolar range), both in U87MG and HEp-2 cells and proved to be non-toxic toward the tested cell lines. In addition, compounds (1<em>R</em>,2<em>S</em>)-<strong>1ha</strong> and (1<em>R</em>,2<em>S</em>)-<strong>1hd</strong> exhibited moderate activity (high micromolar range) against zika virus in Huh7 cell cultures. The C1-epimeric phosphonates (1<em>S</em>,2<em>S</em>)-<strong>1ha</strong> and (1<em>S</em>,2<em>S</em>)-<strong>1 hb</strong> proved to be inactive against the tested viruses, while being highly cytotoxic toward uninfected HEL, Huh-7 and MDCK cell lines. Phosphonic acids derived from the respective diethoxyphosphonyl conjugates showed no activity against the viruses tested, probably due to their poor permeability through cell membranes. In conclusion, our study demonstrates the great potency of the design of conjugates of N1-(phosphonoalkyl)-1,2,3-triazoles and 6-bromoquinazoline-2,4-diones as effective anti-RSV agents and highlights the potential of this compound class as antiviral therapeutics, warranting further structural optimization and <em>in vivo</em> evaluation to develop more potent and selective anti-RSV agents.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"244 ","pages":"Article 106303"},"PeriodicalIF":4.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145421066","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}

{"title":"Inhibitors of pyrimidine synthesis synergize with N4-hydroxycytidine to diminish influenza virus replication","authors":"Leon Schrell ,&nbsp;David Scheibner ,&nbsp;Antje Dickmanns ,&nbsp;Kim M. Stegmann ,&nbsp;Lukas Mathias Michaely ,&nbsp;Annika Graaf-Rau ,&nbsp;Philip Beer ,&nbsp;Andrew Parker ,&nbsp;Sandra Diederich ,&nbsp;Anne Balkema-Buschmann ,&nbsp;Matthias Dobbelstein","doi":"10.1016/j.antiviral.2025.106286","DOIUrl":"10.1016/j.antiviral.2025.106286","url":null,"abstract":"<div><div>Influenza viruses remain a major threat to both human and animal health, with seasonal outbreaks and the risk of pandemics caused by reassortant strains. Antiviral drugs are needed as a complement to vaccines, but resistance often limits their long-term efficacy. N4-hydroxycytidine (NHC), the active form of Molnupiravir, shows potent activity against influenza A viruses (IAVs) in both cell cultures and animal models, with minimal resistance observed.</div><div>Building on prior work in SARS-CoV-2, we investigated whether inhibiting pyrimidine biosynthesis could enhance NHC's antiviral activity against IAVs. The combination of NHC with inhibitors of dihydroorotate dehydrogenase (DHODH) or cytidine triphosphate synthases (CTPS1/2) showed strong synergy. This was evident through reduced cytopathic effects, decreased viral RNA and protein, and a marked absence of infectious virus particles. This synergy was consistent across multiple IAV subtypes, including H1N1, H1N2, H3N2, and H5N1. This synergistic effect was reversed by exogenously supplemented pyrimidine nucleosides, confirming nucleotide depletion as a key mechanism. However, some avian IAVs were less sensitive to the treatment in mammalian cells. The PB2-K627E mutation, affecting the interaction with host factor ANP32, modulated NHC efficacy, implicating viral adaptation in drug responsiveness.</div><div>In a ferret model of H5N1 infection, NHC combined with the CTPS inhibitor STP938 reduced clinical symptoms and lung pathology, with NHC mostly driving antiviral activity and STP938 contributing to disease mitigation. These findings indicate that combining NHC with pyrimidine biosynthesis inhibitors enhances antiviral efficacy against IAVs, especially in rapidly replicating viruses, and may broaden the utility of nucleoside analogues in influenza therapy.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"244 ","pages":"Article 106286"},"PeriodicalIF":4.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231381","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}

{"title":"Mapping the impact of 1′-, 2′- and 4′-nucleotide modifications on the Respiratory Syncytial Virus RNA-dependent RNA polymerase","authors":"Priscila Sutto-Ortiz ,&nbsp;Barbara Selisko ,&nbsp;François Ferron ,&nbsp;Jean-Pierre Sommadossi ,&nbsp;Adel Moussa ,&nbsp;Steven Good ,&nbsp;Bruno Canard ,&nbsp;Etienne Decroly","doi":"10.1016/j.antiviral.2025.106298","DOIUrl":"10.1016/j.antiviral.2025.106298","url":null,"abstract":"<div><div>Human respiratory syncytial virus (RSV) causes pediatric bronchiolitis and severe respiratory illness in the elderly. Despite recent advancements in vaccines and antibody therapies, the search for antiviral agents remains a significant public health challenge. We designed nucleotide analogs (NAs) with ribose modifications to assess their incorporation by the RSV polymerase. Biochemical assays and structural modelling revealed that these NAs effectively disrupt RNA synthesis elongation. They act as chain-terminators via a unique mechanism mediated by the 4′-modification, whereas 2′-F alone has no effect and 1′-modification slows-down RNA synthesis. We evaluated the ability of the polymerase to discriminate between natural nucleotides and NAs through incorporation efficiency/competitive assays, correlating these findings with RSV replication inhibition in infected cell cultures. Our ranking of compounds indicates that cytidine analogs demonstrate the strongest antiviral activity, due to their phosphorylation efficiency and intracellular concentration relative to natural nucleotides as well as their ready incorporation into the growing RNA chain. 4′-modifications are accepted by the RSV polymerase due to structural differences between the active sites of (+) and (−) RNA virus polymerases.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"244 ","pages":"Article 106298"},"PeriodicalIF":4.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285456","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}

{"title":"Biology of hepatitis B virus DNA integration and its impact on antiviral R&D","authors":"Lottida Phondeth ,&nbsp;Thomas Tu","doi":"10.1016/j.antiviral.2025.106305","DOIUrl":"10.1016/j.antiviral.2025.106305","url":null,"abstract":"<div><div>Hepatitis B virus (HBV) drastically increases the risk of developing liver cirrhosis and hepatocellular carcinoma (HCC) in the ∼300 million people with chronic hepatitis B infections. HBV reproduces through an epigenetic circular genome, but can occasionally integrate into the host genome as a replication-defective form. These integrated forms have been reported to contribute to virus persistence and hepatocarcinogenesis. In this review, we highlight the effects of current and novel treatment under development on HBV DNA integrations and provide areas of potential research to develop more effective therapies that target the underlying drivers of persistence and pathogenesis.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"244 ","pages":"Article 106305"},"PeriodicalIF":4.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145457489","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}

{"title":"Inhibition of influenza virus replication by artificial proteins (αReps) targeting its RNA-polymerase","authors":"Mélissa Bessonne ,&nbsp;Jessica Morel ,&nbsp;Quentin Nevers ,&nbsp;Julie Groutsch ,&nbsp;Agathe Urvoas ,&nbsp;Marie Valerio-Lepiniec ,&nbsp;Thibaut Crépin ,&nbsp;Philippe Minard ,&nbsp;Bernard Delmas","doi":"10.1016/j.antiviral.2025.106300","DOIUrl":"10.1016/j.antiviral.2025.106300","url":null,"abstract":"<div><div>Seasonal epidemics and pandemics caused by influenza A viruses still represent a main public health burden in the world. Influenza viruses replicate and transcribe their genome in the nucleus of the infected cells, two functions that are supported by the viral RNA-dependent RNA-polymerase (FluPol) through extensive structural rearrangements and differential interactions with host cell factors. To get insights into its functioning, we screened a phage-display library of biosynthetic proteins (named αReps and built on a rigid alpha-helicoidal HEAT-like scaffold) against the structurally invariant FluPol core and several flexibly-linked domains of the FluPol PB2 subunit. Several αReps specific of the cap binding domain [CBD], the 627-domain and the NLS domain of PB2 displayed FluPol inhibitory and virus neutralization activities when transiently expressed in the cytosol. Furthermore, intracellular ectopic inducible expression of the αReps C3 and F3 (specific of the CBD and the 627-domain, respectively) in influenza virus permissive cells blocked multiplication of viruses representative of the H1N1, H3N2 and H7N1 subtypes, even when induced at late times post-infection. Bispecific αReps constructs (C3-F3 and F3-C3) display a higher FluPol inhibitory activity than their monomeric counterparts. These results suggest that interfering with FluPol structural rearrangements may represent a promising strategy to block virus multiplication and to design new types of antivirals such as dual binders targeting distant sites on FluPol. Furthermore, we found that the 627-domain constitutes a new possible target for engineering influenza antivirals.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"244 ","pages":"Article 106300"},"PeriodicalIF":4.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145353594","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}

{"title":"Rapid generation of a murine RSV infectious model by transducing a conditional knock-in mouse harboring human IGF1 receptor with adenoviral vector","authors":"Rui Xiong ,&nbsp;Yong Wu ,&nbsp;Yuya Wang ,&nbsp;Zhe Qu ,&nbsp;Yanwei Yang ,&nbsp;Susu Liu ,&nbsp;Chen Ling ,&nbsp;Lu Ke ,&nbsp;Nan Xu ,&nbsp;Changgui Li ,&nbsp;Changfa Fan ,&nbsp;Yihong Peng","doi":"10.1016/j.antiviral.2025.106304","DOIUrl":"10.1016/j.antiviral.2025.106304","url":null,"abstract":"<div><div>Human respiratory syncytial virus (RSV) remains the leading viral cause of severe lower respiratory tract disease in infants and young children worldwide. Despite decades of research, RSV vaccine development remains hindered by the lack of animal models that accurately recapitulate pediatric susceptibility and allow rigorous assessment of protective efficacy and safety. Recent studies have identified the human insulin-like growth factor 1 receptor (hIGF1R) as a critical host receptor that facilitates RSV fusion and entry. Using a novel conditional knock-in mouse model, lung-specific hIGF1R expression achieved through Ad5 vector transduction enables rapid generation of a pediatric-relevant mouse model, offering a promising route to close this gap. Following intranasal challenge with RSV A2 (1.62 × 10⁵ TCID₅₀), four-week-old Ad5-hIGF1R mice exhibited higher pulmonary viral loads, marked peribronchiolar and perivascular inflammation, interstitial thickening and a tendency toward alveolar wall coalescence compared with wild-type controls, thereby recapitulating severe pediatric RSV disease. Transcriptomic analysis revealed 12 chemokine genes, upregulated in RSV-infected lungs of Ad5-hIGF1R mice relative to mock controls, that are involved in immune-inflammatory pathways and may serve as practical biomarkers for detecting dysregulated host responses during vaccine or antiviral-drug assessment. Furthermore, A mid-dose prefusion F (pre-F) vaccination regimen significantly reduced viral loads and moderately attenuated neutrophil infiltration in the lungs of Ad5-hIGF1R mice. In summary, the young Ad5-hIGF1R mice demonstrate that hIGF1R expression enhances RSV replication and immunopathology <em>in vivo</em>. This model not only overcomes the limited RSV susceptibility of conventional young mice but also provides a platform for evaluating RSV vaccines.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"244 ","pages":"Article 106304"},"PeriodicalIF":4.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145421064","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}