Journal of Virology最新文献

{"title":"Interleukin-17A directly triggers Epstein-Barr virus lytic reactivation in latency I human B-cell models.","authors":"Janardhan Avilala, Hirotomo Dochi, Ramsy Abdelghani, David Becnel, Grace Maresh, Xin Zhang, Li Li, Mark Sides, Gilbert Morris, Hong Liu, Zhen Lin","doi":"10.1128/jvi.00813-26","DOIUrl":"10.1128/jvi.00813-26","url":null,"abstract":"<p><p>Epstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus implicated in inflammatory, malignant, and autoimmune diseases. Although EBV toggles between latent and lytic states, the host cues controlling this switch remain incompletely defined. Interleukin-17A (IL-17A), a signature Th17 cytokine, is enriched in EBV-associated inflammatory settings, and EBV products can augment IL-17A responses. Whether IL-17A directly regulates the EBV life cycle has remained unknown. Here, we show that IL-17A alone is sufficient to induce EBV lytic reactivation in latency I human B-cell models. IL-17A increased BZLF1/Zta, activated the BZLF1 promoter (Zp), induced early and late lytic genes and proteins, and promoted DNase-resistant EBV DNA release and infectious virion production. Mechanistically, IL-17A activated NF-κB and ERK/p38 MAPK signaling, including phosphorylation of p65, ERK1/2, and p38. IL-17RA blockade reduced IL-17A-induced signaling and lytic reactivation, and pharmacologic inhibition of NF-κB or p38 MAPK signaling attenuated EBV reactivation. Among IL-17 family members tested, only IL-17A induced reactivation. RNA-seq provided a transcriptome-wide view of the viral and cellular response to IL-17A, revealing broad EBV lytic transcription and inflammatory, NF-κB-associated, and B-cell activation programs. IL-17A responsiveness was latency- and cell-state restricted: latency I B-cell models responded, whereas latency II/III, lymphoblastoid, and EBV-positive epithelial models did not. Subinducing IL-17A (1 ng/mL) was insufficient alone but enhanced B-cell receptor-mediated reactivation, suggesting threshold-lowering activity in inflammatory B-cell niches. Together, these findings identify IL-17A as a receptor-linked inflammatory cue for EBV lytic entry and provide the first demonstration that IL-17A alone directly triggers EBV lytic reactivation in human cells.IMPORTANCEEpstein-Barr virus (EBV) persists for life by maintaining latency with lytic reactivation, yet the inflammatory cues that initiate this switch remain poorly defined. Here, we identify interleukin-17A (IL-17A), a Th17 cytokine, as a direct trigger of EBV lytic reactivation in latency I human B-cell models. IL-17A activates IL-17RA-linked NF-κB/MAPK signaling, induces BZLF1/Zta and downstream lytic genes, and promotes DNase-resistant EBV DNA release and infectious virion production. IL-17RA blockade and inhibition of NF-κB/p38 MAPK signaling reduce reactivation, supporting a receptor-linked mechanism rather than nonspecific stress. Subinducing IL-17A (1 ng/mL) was insufficient to reactivate EBV alone but enhanced B-cell receptor-mediated reactivation, suggesting threshold-lowering activity in inflammatory B-cell niches. The response is restricted by latency and cell state, indicating that IL-17A signaling must be coupled to a permissive EBV lytic switch. These findings connect Th17-skewed inflammation to EBV reactivation burden and suggest that IL-17A/IL-17R signaling may infl","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0081326"},"PeriodicalIF":4.1,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149039641","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":"Beyond polio: advanced human <i>in vitro</i> models for studying non-polio enterovirus pathogenesis.","authors":"Ashley Kelly Pereirinha da Silva, Bjoern Meyer, Lisa Bauer","doi":"10.1128/jvi.01699-25","DOIUrl":"10.1128/jvi.01699-25","url":null,"abstract":"<p><p>While efforts to eradicate poliovirus are ongoing, non-polio enteroviruses (NPEV) continue to pose a substantial public health threat. NPEVs cause a wide range of diseases, from mild self-limiting infections to severe respiratory, neurological, and cardiac complications, with the highest burden occurring in children and immunocompromised populations. Recent advances in human stem cell-derived cultures, organoids, air-liquid interface systems, and assembloids have transformed the study of NPEV pathogenesis by providing physiologically relevant models that recapitulate human tissue architecture, cellular complexity, and host responses. In this review, we discuss how these advanced <i>in vitro</i> systems have enhanced our understanding of the determinants of viral tropism, including receptor usage, epithelial polarity, tissue-specific susceptibility, and viral genetic variation. We further highlight insights into serotype-dependent differences in innate immune responses, tissue injury, and dissemination mechanisms. Finally, we explore the potential of these models for antiviral discovery and personalized therapeutic development, emphasizing their value for advancing both fundamental and translational NPEV research.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0169925"},"PeriodicalIF":4.1,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149081150","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":"GSK3 maintains NSP12 stability to promote bat-origin swine acute diarrhea syndrome coronavirus infection.","authors":"Maowen Sun, Cong Yuan, Yueyue Duan, Lei Shi, Yu Zhang, Luyao Li, Wenquan Mao, Haixue Zheng, Qi Wang","doi":"10.1128/jvi.00683-26","DOIUrl":"10.1128/jvi.00683-26","url":null,"abstract":"<p><p>Bat-origin swine acute diarrhea syndrome coronavirus (SADS-CoV) causes diarrhea and death in piglets and also poses a cross-species transmission risk due to its broad host cell tropism. In the absence of commercial vaccines or therapeutics, identifying the host factors exploited by SADS-CoV may provide potential targets for antiviral therapies. Inhibition of glycogen synthase kinase 3 (GSK3) restricts diverse coronavirus replication by targeting the N protein and disrupting its phosphorylation. Here, we identified GSK3 as a crucial host factor for SADS-CoV RNA synthesis. Both GSK3 deficiency and treatment with a classical GSK3 inhibitor, lithium chloride (LiCl), strongly impaired SADS-CoV dsRNA synthesis. LiCl treatment did not alter electrophoretic mobility or expression of SADS-CoV N protein in N-transfected Huh7 cells but significantly reduced NSP12 protein levels. The absence of GSK3 led to the proteasomal degradation of NSP12 to reduce viral RNA synthesis. However, GSK3 interacted with ubiquitin-specific peptidase 27X (USP27X) and promoted the USP27X-mediated deubiquitination of NSP12, thereby enhancing NSP12 stabilization and facilitating viral RNA synthesis. LiCl not only protected neonatal mice from lethal SADS-CoV challenge but also exhibited a notable broad-spectrum antiviral effect against PEDV and TGEV. Our findings demonstrate that GSK3-mediated NSP12 stabilization is essential for SADS-CoV RNA synthesis, underscoring the potential of GSK3 as a broad-spectrum antiviral target for emerging and re-emerging swine coronaviruses.IMPORTANCEZoonotic transmission of coronaviruses continues to pose a significant threat to human populations. Swine acute diarrhea syndrome coronavirus (SADS-CoV) has been identified as a potentially high-risk emerging coronavirus pathogen that could adversely affect the global economy and human health. However, the replication mechanisms of SADS-CoV remain largely unexplored. Our study demonstrates that GSK3 stabilizes NSP12 by interacting with USP27X, thereby enhancing the synthesis of SADS-CoV dsRNA. LiCl, a GSK3 inhibitor, exhibits broad-spectrum antiviral activity against swine enteric alphacoronaviruses. Our work is distinguished for the first time by the GSK3-USP27X regulatory axis that controls the stability of NSP12 and indicates that GSK3 is a promising therapeutic target for the development of broad-spectrum antiviral drugs against emerging or re-emerging swine coronaviruses.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0068326"},"PeriodicalIF":4.1,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149081271","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":"Protein kinase D1 regulates innate immune signaling pathways to promote hepatitis C virus replication.","authors":"Jiyoung Lee, Yu-Chen Chuang, Johanna Ahn Lee, J-H James Ou","doi":"10.1128/jvi.00693-26","DOIUrl":"10.1128/jvi.00693-26","url":null,"abstract":"<p><p>Hepatitis C virus (HCV) has developed multiple means to disrupt host innate immune response to promote its replication. Protein kinase D1 (PKD1) is a serine/threonine kinase involved in cell proliferation and lipid metabolism. By analyzing the effect of PKD1 on HCV replication, we found that HCV activated PKD1 via protein kinase C (PKC) early in infection and induced the cleavage of PKD1 at later timepoints of infection via caspase-3. PKD1 silencing had no effect on HCV entry, but it reduced HCV RNA levels in cells, indicating an important role of PKD1 in promoting HCV replication. PKD1 silencing also induced the expression of interferons (IFNs) and IFN-stimulated genes (ISGs) and augmented the HCV-induced TNF-α expression, which enhanced the IFN response. Interestingly, the induction of inflammasomes was compromised in HCV-infected cells in the absence of PKD1, indicating an important role of PKD1 in promoting the inflammasomal response. Taken together, our results indicated that HCV activated PKD1 to suppress the IFN response and TNF-α signaling and in the meantime induce the inflammasomal response. Our results, thus, revealed an interesting interplay between HCV and host innate immune responses and an important role of PKD1 in this intricate interplay.</p><p><strong>Importance: </strong>Hepatitis C virus (HCV) establishes chronic infection in most patients that it infects, and this chronic infection can lead to severe liver diseases including steatosis, cirrhosis, and hepatocellular carcinoma. PKD1 is a multifunctional protein that regulates lipid metabolism, cell proliferation, and cellular apoptosis. In this report, we investigated the relationship between HCV and PKD1. We found that HCV could activate PKD1 to suppress interferon response and TNF-α signaling to promote its replication and in the meantime enhance the inflammasomal response. These effects of HCV on PKD1 provide important insights for understanding the mechanism of HCV persistence and pathogenesis in patients.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0069326"},"PeriodicalIF":4.1,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912538","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":"Respiratory syncytial virus-induced ADAM17 activity controls maintenance of epithelial barrier integrity and promotes syncytium formation.","authors":"Robert Meineke, Marie-Christin Knittler, Rajarshee Tagore, Nele Engling, Martin Ludlow, Albert D M E Osterhaus, Guus F Rimmelzwaan","doi":"10.1128/jvi.01150-26","DOIUrl":"10.1128/jvi.01150-26","url":null,"abstract":"<p><p>Respiratory syncytial virus (RSV) infection causes epithelial injury, barrier disruption, and formation of syncytia in human lung tissue; however, the regulatory host defense mechanisms involved remain poorly defined. ADAM17 is a multifunctional sheddase implicated in inflammatory lung disease and is considered a potential therapeutic target during viral infections. Here, we show that RSV infection induces ADAM17 activity through PKC- and ERK-dependent signaling, increasing surface ADAM17 levels and sheddase activity. Genetic loss or pharmacological inhibition of ADAM17 reduced RSV-induced formation of syncytia, post-entry viral spread, and viral titers. This identifies ADAM17 as a host factor that supports viral dissemination. ADAM17 deficiency simultaneously exacerbated RSV-induced epithelial injury, characterized by loss of intercellular cohesion, impaired barrier function, increased paracellular permeability, and enhanced cytotoxicity. RSV-induced ADAM17 activity promoted the release of multiple epithelial growth factor receptor (EGFR) ligands. Supplementation with recombinant amphiregulin partially restored barrier function in infected ADAM17-deficient cells. Consistent with these functional effects, ADAM17 deficiency was associated with the loss of epithelial differentiation-associated transcriptional programs and increased expression of inflammatory genes. These findings indicate that ADAM17 plays a dual role in RSV infection. It facilitates syncytial viral spread, while preserving epithelial integrity through autocrine EGFR signaling. Thus, ADAM17 activity represents a biological trade-off between viral dissemination and tissue protection, indicating that therapeutic ADAM17 inhibition may reduce viral spread at the cost of aggravating epithelial damage.IMPORTANCEDuring respiratory syncytial virus (RSV) infection, the airway epithelium must maintain barrier integrity while responding to virus-induced syncytium formation and tissue damage. It is poorly understood which host factors balance tissue preservation against viral replication and spread. Here, we demonstrate that the host cellular metalloproteinase ADAM17 is activated upon RSV infection. While RSV-induced ADAM17 activity promotes syncytium formation and viral spread, it concurrently controls the maintenance of epithelial barrier integrity, preserves cell survival, and inhibits hyperinflammatory signaling. By demonstrating that ADAM17 has a dual mode of action controlling both viral propagation and epithelial barrier resilience, this work uncovers a central trade-off: the same host factor exploited by RSV for dissemination is essential for protecting airway tissue. Consequently, targeting ADAM17 for antiviral therapy presents major challenges, as blocking viral spread may compromise vital epithelial defenses.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0115026"},"PeriodicalIF":4.1,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149069909","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":"Viral control of translation: rise of the ribosome.","authors":"Peter S Shen, Derek Walsh","doi":"10.1128/jvi.01282-26","DOIUrl":"10.1128/jvi.01282-26","url":null,"abstract":"<p><p>Viruses have evolved a myriad of strategies to manipulate their host's protein synthesis machinery, studies of which uncovered many founding principles of translational control. Decades of research have established our now-extensive understanding of how these pathogens target the array of translation factors that recruit ribosomes and regulate scanning, start site selection, decoding, and termination. Meanwhile, the ribosome itself was largely regarded as a code-reading machine that lacks regulatory influence. Recent advances in cryo-electron microscopy and quantitative proteomics have upended this viewpoint by revealing the remarkable conformational and compositional plasticity that gives rise to functionally diverse and translationally selective ribosome populations in mammalian cells. Here, we discuss how viruses are once again at the forefront of this emerging field, often bypassing or rewiring host translation factors while directly controlling the ribosome's composition and intrinsic motions to selectively promote their non-canonical modes of translation. We offer cautionary perspectives on extra-ribosomal functions of ribosomal proteins, while highlighting the emergence of the 40S head domain as a dynamic platform targeted to control various translation processes, ranging from initiation to frameshifting, that expand viral coding capacity. Overall, we chart the rise of the ribosome from a passive player to an active regulatory hub at the center of viral translational control strategies.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0128226"},"PeriodicalIF":4.1,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148963500","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":"Internal poly(A) replacement strategy within 3' UTR for live-attenuated tick-borne encephalitis virus.","authors":"Qiu-Yan Zhang, Zhe-Rui Zhang, Cheng-Lin Deng, Jing Wang, Hong-Qing Zhang, Han-Qing Ye, Ya-Nan Zhang, Bo Zhang","doi":"10.1128/jvi.00781-26","DOIUrl":"10.1128/jvi.00781-26","url":null,"abstract":"<p><p>Tick-borne encephalitis virus (TBEV), a prominent orthoflavivirus transmitted by ticks, poses a risk of potentially fatal encephalitis in humans. Currently, the only available inactivated vaccines have limited usage, underscoring the need for developing novel vaccine strategies. The 3' untranslated region (UTR) of TBEV can be divided into variable and conserved regions, where structured RNA elements play crucial roles in viral replication and virulence. In this study, we found that deleting sequences in both the variable region and most of the conserved region within the 3'UTR eliminated viral replication. However, inserting a poly(A) tract effectively restored viral propagation. Notably, the recovered virus variants, Δ1-642/poly(A), exhibited high attenuation in mice. A single-dose immunization with Δ1-642/poly(A) induced robust TBEV-specific IgG, neutralizing antibody, and T-cell immune responses, providing complete protection against lethal challenges with wild-type virus. Collectively, our findings demonstrate that poly(A) replacement represents a viable strategy for developing live-attenuated TBEV vaccines.IMPORTANCEOrthoflaviviruses, encompassing mosquito-borne dengue virus (DENV), yellow fever virus (YFV), Zika virus (ZIKV), West Nile virus (WNV), and tick-borne encephalitis virus (TBEV), represent a substantial global public health and economic burden. The 3' UTR is critical for viral replication and pathogenesis, as exemplified by the ongoing clinical development of the tetravalent Butantan dengue vaccine (with deletion in 3' UTR). Our previous study on WNV-poly(A) variants proposed a novel live-attenuated vaccine design via 3' UTR engineering, yet its broad applicability remained unclear due to extensive 3' UTR heterogeneity. In this study, we successfully rescued a TBEV poly(A) virus using an analogous strategy. This virus was highly attenuated in mice, and a single immunization provided long-term complete protection against lethal wild-type virus challenge. Collectively, our data validate the poly(A) replacement approach as a potentially universal platform for developing live-attenuated vaccines against both mosquito-borne and tick-borne orthoflaviviruses.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0078126"},"PeriodicalIF":4.1,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148977073","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":"Antigenic and structural analysis of the influenza hemagglutinin lateral patch.","authors":"Jordan I Lemus-Reyes, Monica L Fernández-Quintero, Edgardo Ayala, Olivia M Swanson, Marina R Good, Wei Ji, Devika Suja, Julianna Han, Andrew B Ward, Jenna J Guthmiller","doi":"10.1128/jvi.01265-26","DOIUrl":"10.1128/jvi.01265-26","url":null,"abstract":"<p><p>The lateral patch epitope of the H1 hemagglutinin (HA) was a dominant target of antibodies following exposure to the 2009 pandemic H1N1 virus. However, the conservation and mechanisms of antigenic drift in the lateral patch remain unresolved. Here, we used lateral patch-specific monoclonal antibodies (mAbs) to understand the antigenicity of the lateral patch of human, avian, and swine H1N<i>x</i> viruses spanning from 1918 to 2022. We found that lateral patch-specific mAbs demonstrated broad binding to pre-2009 H1N1 viruses and to the pandemic 2009 H1N1. However, we identified discrete mutations that drove multiple antibody evasion pathways for lateral patch-targeting mAbs in post-2009 H1N1 viruses. Despite this, we observed that the lateral patch remains well conserved across enzootic sources, suggesting that existing lateral patch antibodies could protect against a future zoonotic H1N<i>x</i> pandemic. Together, these data support that the lateral patch remains an attractive target for pandemic preparedness against emergent H1N<i>x</i> viruses.IMPORTANCESeasonal influenza viruses continually undergo antigenic drift to evade antibody-mediated immunity, yet how individual antibody specificities shape this evolution remains poorly understood. We investigated the conservation and antigenic evolution of the H1 hemagglutinin (HA) lateral patch, an epitope targeted by broadly neutralizing antibodies. Using human monoclonal antibodies, we found that the lateral patch had remained highly conserved across nearly a century of human and animal influenza virus circulation but has undergone antigenic drift multiple times in pre- and post-2009 seasonal H1N1 viruses. Structural and mutational analyses revealed how these substitutions alter antibody recognition and shape the genetic features of lateral patch-targeting antibodies across individuals born in different eras. The lateral patch is also conserved among swine and avian H1N<i>x</i> viruses, highlighting its potential as a target of protective immunity against pandemic H1N<i>x</i> viruses. These findings provide a comprehensive framework for understanding antibody-driven evolution within a broadly conserved influenza virus epitope.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0126526"},"PeriodicalIF":4.1,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149025295","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":"Bile and capsid variation coregulate histo-blood group antigen recognition and serum neutralization potency in GII.12 human norovirus.","authors":"Michael L Mallory, Dev K Patel, Lily M Parsons, Miranda L Hubbard, Juyeon Park, Isaac L Hughes, Paul D Brewer-Jensen, Mark R Zweigart, Yaoska I Reyes, Matthew C Wolfgang, Lisa C Lindesmith, Ralph S Baric","doi":"10.1128/jvi.01338-26","DOIUrl":"10.1128/jvi.01338-26","url":null,"abstract":"<p><p>Human norovirus (HuNoV) is a leading cause of acute gastroenteritis, with young children and the elderly bearing the greatest disease burden. GII strains cause the majority of HuNoV outbreaks globally, with host susceptibility influenced by genetic polymorphisms that regulate mucosal expression of histo-blood group antigen (HBGA) binding ligands. HuNoV viral capsid (VP1) diversity in residues adjacent to the conserved HBGA binding pocket selectively stabilizes ligand interactions. Additionally, select HuNoV capsids demonstrate bile-influenced conformational plasticity, further enabling HBGA engagement. Combined, these factors have the potential to enhance the breadth of binding of HuNoV to HBGAs, driving population susceptibility. Here we characterized two GII.12 outbreak strains that co-circulated cotemporaneously and were divergent at five key VP1 sites. Mutational analysis demonstrated amino acids at VP1 positions 373 and 392 coregulate HBGA ligand binding. Serological analysis demonstrated minimal antigenic impact at these positions. Broader GII comparisons demonstrated variable impacts of bile. Bile improved GII.2 and GII.12 binding to HBGA, in contrast to GII.4, GII.3, and GII.6. Further, bile reduced surrogate neutralizing antibody potency for GII.2 and GII.12 but not GII.4 and GII.6 strains. Collectively, these studies suggest that HuNoV bile-dependence is not a general feature of GII norovirus, but instead can be genotype or strain specific. These data inform how select GII HuNoV strains can modulate capsid residues linked to host-ligand and immune recognition, providing potential mechanistic evidence for continual viral circulation.</p><p><strong>Importance: </strong>Human norovirus-host interactions are complex, influenced by viral diversity, host-ligand expression profiles, and the gastrointestinal environment. Periodically, outbreaks of endemic human noroviruses, like GII.12, demonstrate genetic diversity between viral strains of a genotype. Exploring this, two GII.12 outbreak strains were used to model the effects of genetic changes on the viral capsid ligand and antibody binding. Residue changes between the two strains modulated affinity for histo-blood group antigens that could be compensated for by addition of bile. Although bile improved HBGA-binding, it reduced serum and monoclonal antibody neutralization potency to GII.12. These observations demonstrate the balanced impact of bile-mediated viral capsid conformational plasticity in ligand recognition and potential immune evasion for select GII genotypes. Bile had similar effects for GII.2 HuNoV, but did not impact GII.6 or GII.4 HuNoV HBGA-binding and serum-ligand blocking potency, indicating that GII HuNoV strains potentially utilize multiple mechanisms to ensure host breadth and antigenic diversity.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0133826"},"PeriodicalIF":4.1,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149039469","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":"Limited adaptive mutations but deterministic genome formula variation in bluetongue virus.","authors":"Yannis Moreau, Patricia Gil, Antoni Exbrayat, Ignace Rakotoarivony, Emmanuel Bréard, Corinne Sailleau, Cyril Viarouge, Stephan Zientara, Giovanni Savini, Maria Goffredo, Giuseppe Mancini, Etienne Loire, Serafin Gutierrez","doi":"10.1128/jvi.00983-26","DOIUrl":"https://doi.org/10.1128/jvi.00983-26","url":null,"abstract":"<p><p>Arthropod-borne viruses or arboviruses alternate between vertebrates and arthropods, facing distinct selection pressures in each host. Surprisingly, mechanisms facilitating host alternation remain unstudied. Here, we investigate two phenomena potentially facilitating host alternation in bluetongue virus (BTV): adaptive mutations and genome formula variation (GFV; i.e., differences in segment copy numbers). First, we searched for mutations indicative of host adaptation in cattle, sheep, and midges infected during an epizootic. No mutation was fixed in all samples of a given host. Thus, adaptive mutations may not be a major mechanism facilitating host alternation in the studied epizootic. Second, we investigated the relationship between GFV and a proxy of viral fitness, namely, head infection in midges. We analyzed the genome formula (GF) in <i>Culicoides imicola</i> midges, either with or without head infection 10 days after oral inoculation. GFs differed between dissemination groups, suggesting a correlation between GF and head infection. Finally, we investigated the mechanisms underlying GF generation. Currently, two scenarios have been proposed: random generation followed by selection or directed generation through molecular mechanisms. To limit the influence of selection, we analyzed the GF after a single replication cycle in cell culture. GFs converged toward specific values across replicates. Moreover, GFs differed between arthropod and vertebrate cells. Thus, GF generation does not seem purely stochastic and is probably influenced by host-specific mechanisms. Overall, our findings highlight GFV as a mechanism potentially facilitating host alternation of BTV, and they do not strongly support an involvement of mutations in the same phenomenon.IMPORTANCEArthropod-borne viruses are major public health concerns worldwide. These viruses follow a complex cycle involving an alternation between arthropods and vertebrates. Surprisingly, little is known about the mechanisms that could facilitate this alternation. Understanding such mechanisms could aid the development of antiviral strategies. Here, using bluetongue virus as a model, we investigated two potential mechanisms facilitating alternation. These mechanisms are adaptive mutations and genome formula variation (GFV). We found limited evidence for host-specific parallel mutations in natural populations from a single epizootic. In contrast, we observed a potential link between GFV and viral fitness. Moreover, our results suggest that molecular mechanisms generate host-specific genome formulas from the first round of cell infection.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0098326"},"PeriodicalIF":4.1,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149182779","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}