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":"2025-10-12","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":"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":"2025-10-11","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":"Mapping the impact of 1'-, 2'- and 4'-nucleotide modifications on the Respiratory Syncytial Virus RNA-dependent RNA polymerase.","authors":"Priscila Sutto-Ortiz, Barbara Selisko, François Ferron, Jean-Pierre Sommadossi, Adel Moussa, Steven Good, Bruno Canard, Etienne Decroly","doi":"10.1016/j.antiviral.2025.106298","DOIUrl":"10.1016/j.antiviral.2025.106298","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":" ","pages":"106298"},"PeriodicalIF":4.0,"publicationDate":"2025-10-11","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":"Small molecule HBV RNA destabilizing drugs: Drugs of the future or compounds from the past?","authors":"Timothy M Block, Dimitar Gotchev, Yanming Du","doi":"10.1016/j.antiviral.2025.106288","DOIUrl":"10.1016/j.antiviral.2025.106288","url":null,"abstract":"<p><p>Small-molecule HBV RNA destabilizing agents, such as the dihydroquinolizinones (DHQs), were first disclosed in a patent filing in 2015 and in peer reviewed literature in 2018. These compounds inhibit Poly-adenylating Polymerases 5 and 7 (PAPD5/7) and represent a novel antiviral strategy and their ability to degrade hepatitis B surface antigen (HBsAg) in cell culture and animal models generated considerable excitement and commercial interest. However, extrahepatic toxicity observed in preclinical and Phase I studies led to the discontinuation of several development programs. The subsequent emergence of liver-targeted PAPD5/7 inhibitors with improved safety profiles has rekindled interest in this therapeutic approach. Yet, with the apparent success of other investigational antivirals in reducing HBsAg levels, such as siRNAs, antisense oligonucleotides, and in at least one example, capsid assembly modulators (CAMs), questions remain as to whether RNA destabilizers still have a role in managing chronic hepatitis B (CHB). This review describes the current status of PAPD5/7 inhibitor development, evaluates the advantages and limitations of the approach, and considers potential strategies for integrating this class of molecules with other HBV therapies.</p>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":" ","pages":"106288"},"PeriodicalIF":4.0,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145257217","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":"Ciclopirox suppresses poxvirus replication by targeting iron metabolism","authors":"Anil Pant ,&nbsp;Djamal Brahim Belhaouari ,&nbsp;Lara Dsouza ,&nbsp;D.M. Nirosh Udayanga ,&nbsp;Zhengqiang Wang ,&nbsp;Zhilong Yang","doi":"10.1016/j.antiviral.2025.106290","DOIUrl":"10.1016/j.antiviral.2025.106290","url":null,"abstract":"<div><div>Poxviruses remain a significant global health concern, necessitating the development of novel antiviral strategies. Through high-throughput screening, we previously identified ciclopirox (CPX), an FDA-approved antifungal, as a hit that inhibits vaccinia virus (VACV) replication. Here, we further characterized its antiviral activity and mechanism of action using human primary fibroblasts. CPX significantly reduced VACV titers without reducing host cell viability, with an EC₅₀ in the sub-micromolar range and a CC₅₀ &gt; 500 μM. Rescue experiments demonstrated that CPX inhibits viral replication primarily through chelation of intracellular Fe³⁺ and, to a lesser extent, Fe²⁺, as evidenced by partial restoration of viral replication with ferric ammonium citrate supplementation. Furthermore, overexpression of the iron-dependent enzymes RRM2 and the VACV-encoded F4L reduced the inhibitory effect of CPX, indicating that these host and viral proteins are affected by CPX treatment. Moreover, CPX treatment suppressed cowpox virus and monkeypox (mpox) virus replication <em>in vitro</em>. It also reduced VACV titers in <em>ex vivo</em> mouse lung tissue. These findings highlight host iron metabolism as a critical determinant of poxvirus replication and identify CPX as a promising antiviral candidate against multiple orthopoxviruses.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"244 ","pages":"Article 106290"},"PeriodicalIF":4.0,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145257245","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":"2025-10-09","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":"Composition, three-dimensional structure and formation mechanism of the foot and mouth disease virus replication complexes","authors":"Bonan Lv ,&nbsp;Xingran Wang ,&nbsp;Ying Zhou ,&nbsp;Zihan Su ,&nbsp;Yidan Sun ,&nbsp;Yingying Yang ,&nbsp;Yang Lu ,&nbsp;Zishu Pan ,&nbsp;Xiao-Feng Tang ,&nbsp;Chao Shen","doi":"10.1016/j.antiviral.2025.106287","DOIUrl":"10.1016/j.antiviral.2025.106287","url":null,"abstract":"<div><div>Positive-sense RNA virus infections induce vesicle formation within host cells to support RNA replication. By extracting and purifying foot-and-mouth disease virus (FMDV) replication complexes and comparing host cells and replication complexes through targeted lipidomics and proteomics analyses, we found that FMDV enriches host cell proteins and polyunsaturated fatty acids in viral replication complexes (VRCs) to facilitate their formation. On the basis of these findings, we propose a model in which VRCs progress from single-membrane vesicles to multi-membrane vesicles (MMVs) during FMDV replication, a process that requires coordinated contributions of host cell proteins and organelle membranes derived from multiple organelles. Our study showed that, as infection advances, FMDV converts single-membrane vesicles (SMVs) into MMVs, which aggregate to expand the surface area of the replication platform and enhance replication efficiency. These membrane structures function in FMDV replication; the endoplasmic reticulum undergoes curling and folding to support VRC assembly. Additionally, some VRCs possess outward-facing openings that permit material exchange. These findings reveal unexpected similarities between FMDV and distantly related positive-strand RNA viruses, suggesting that shared host cellular pathways are exploited to construct membrane-bound replication factories.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"244 ","pages":"Article 106287"},"PeriodicalIF":4.0,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273387","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, David Scheibner, Antje Dickmanns, Kim M Stegmann, Lukas Mathias Michaely, Annika Graaf-Rau, Philip Beer, Andrew Parker, Sandra Diederich, Anne Balkema-Buschmann, Matthias Dobbelstein","doi":"10.1016/j.antiviral.2025.106286","DOIUrl":"10.1016/j.antiviral.2025.106286","url":null,"abstract":"<p><p>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. 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. 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.</p>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":" ","pages":"106286"},"PeriodicalIF":4.0,"publicationDate":"2025-10-03","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":"Design, synthesis, and biological evaluation of novel 6-aminoalkyl- and 7-heteroaryl substituted 7-deazapurine nucleoside analogs against SARS-CoV-2 replication.","authors":"Guoqiang Yao, Xue Shi, Hao Jiang, Anna Duan, Jiancun Zhang","doi":"10.1016/j.antiviral.2025.106246","DOIUrl":"10.1016/j.antiviral.2025.106246","url":null,"abstract":"<p><p>Despite the declaration by the WHO on May 5th of 2023 that the COVID-19 epidemic no longer constitutes a Public Health Emergency of International Concern (PHEIC), it continues to pose a significant threat to human health due to ongoing viral mutations. Although multiple vaccines and drugs have received approval for the prevention and treatment of COVID-19, effectively controlling the epidemic continues to be challenging, emphasizing the necessity for the development of new and more effective antivirals. In this work, we report the design and synthesis of a series of novel 7-alkynyl-7-deazapurine nucleoside analogs and some of their corresponding prodrugs as potential inhibitors of SARS-CoV-2 replication. The biological activities were evaluated and a reasonable structure-activity relationship (SAR) was revealed. Among the compounds, compound 54 (EC₅₀ = 0.71 μM) and 30c (EC₅₀ = 0.66 μM) may serve as potential candidates for further development.</p>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":" ","pages":"106246"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144774554","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":"Modeling neurotropic virus infection with functional human neural spheroids as a platform for high-throughput antiviral screening and pathogenesis.","authors":"Angelica Medina, Yu-Chi Chen, Jiajing Zhang, Sarah C Ogden, Samantha Cotsmire, Harshad D Vishwasrao, Marc Ferrer, Emily M Lee","doi":"10.1016/j.antiviral.2025.106248","DOIUrl":"10.1016/j.antiviral.2025.106248","url":null,"abstract":"<p><p>Neurotropic arboviruses pose significant threats to human health due to their ability to infect the central nervous system (CNS). Despite the significant impact on public health, mechanisms underlying neuropathogenesis remains poorly understood, and the development of effective antivirals has been hampered by the lack of predictive, high-throughput (HT) infection platforms that can replicate in vivo disease features to drive early drug discovery. To address this gap, we developed a human-based, HT-compatible, functional viral disease neural spheroid model assembled from human induced pluripotent stem cell (hiPSC)-differentiated neurons and astrocytes as a platform for studying virus infection and the development of HT screening (HTS)-compatible assays for drug discovery. Here, we investigated eight high impact species belonging to either the Bunyaviricetes class or Togaviridae family and evaluated infectability on neural spheroids, followed by characterization of neural activity dysregulation and induced disease. We found that neural spheroids support productive infection, with virus- and time-dependent changes in disease profiles. Transcriptomic changes induced by two representative members, LACV and CHIKV, revealed a highly pro-inflammatory response in LACV infected spheroids whereas CHIKV-infection induced neurodegenerative profiles. Finally, we evaluated antiviral and anti-neural dysfunction activity of interferon-alpha as well as tested the small molecule gemcitabine against CHIKV as a proof-of-concept for HT antiviral compound screening. Together, our data establishes the viral-neural spheroids as a valuable platform that supports productive infection by high impact neurotropic viruses, and this platform can be used to both investigate viral pathogenesis and support therapeutics discovery and development.</p>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":" ","pages":"106248"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144774555","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}