Journal of Virology最新文献

{"title":"Human infection with pseudorabies virus: review of evidence, risk assessment, and future directions.","authors":"Herman W Favoreel","doi":"10.1128/jvi.00080-26","DOIUrl":"https://doi.org/10.1128/jvi.00080-26","url":null,"abstract":"<p><p>Pseudorabies virus (PRV) is an alphaherpesvirus with a broad host range, with the pig as its natural host. Although PRV can use human cell surface receptors for cell entry, humans and higher primates have been considered as refractory or showing very limited susceptibility to PRV infection. Between 1914 and 2011, only 17 cases of suspected human PRV infection were described, typically displaying temporal and mild/intermediate disease symptoms, mostly consisting of severe itching. No neurological complications were reported. In addition, in 1970, one researcher conducted a repetitive PRV self-inoculation experiment, which resulted in neither symptoms nor seroconversion. However, since 2011 and mostly based on next-generation sequencing on cerebrospinal fluid, 34 human cases of suspected PRV infection have been reported, all of which were linked with severe, life-threatening encephalitis and/or visual impairment. All these cases were reported in China, where there has been a concomitant surge in outbreaks of PRV strains that show genetic differences compared to classical PRV strains. All suspected recent cases of human PRV infection had (occupational) contact with raw pig meat and often had skin damage on the hands or fingers, or direct eye contact with potentially PRV-infected material. Importantly, human-to-human PRV infection has never been reported. Although the risk for human PRV infection remains very low, these recent developments should guide increased efforts to eradicate PRV from domestic pig populations, increase protection of individuals at risk, and increase research on improved diagnostics, effective antivirals, and a better understanding of the host and viral factors that determine human susceptibility or resistance to PRV infection.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0008026"},"PeriodicalIF":3.8,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147774811","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":"Pvf/Pvr signaling relieves white spot syndrome virus-induced lipid consumption to inhibit viral infection in shrimp.","authors":"Zi-Hua Cheng, Ping-Ping Liu, Ze-Xuan Fan, Meng Zhang, Shu-Dian Zhang, Yuan-Ning Li, Dong-Wei Kang, Xian-Wei Wang","doi":"10.1128/jvi.00182-26","DOIUrl":"https://doi.org/10.1128/jvi.00182-26","url":null,"abstract":"<p><p>Platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF)-related factors (Pvfs) are highly conserved and widespread growth factors whose signaling is mediated by the PDGF/VEGF-related receptor (Pvr). Pvf/Pvr signaling is involved in the regulation of development, immunity, and metabolism of organisms and can be a key therapeutic target for a variety of clinical diseases. However, the functions and mechanisms of Pvf/Pvr signaling in viral infections are largely unknown. In the present study, we found that Pvf/Pvr family members, MjPvf2/MjPvr3, inhibit white spot syndrome virus (WSSV) infection by regulating lipid metabolism in the kuruma shrimp (<i>Marsupenaeus japonicus</i>). WSSV infection caused a pronounced reduction in triglyceride content, whereas the activation of MjPvf2/MjPvr3 signaling relieved lipid consumption and suppressed viral infection. Mechanistically, WSSV infection enhanced MjPvf2/MjPvr3 signaling, leading to the activation of extracellular signal-regulated kinase (ERK) and sterol regulatory element-binding protein (SREBP), and subsequent induction of hydroxysteroid dehydrogenase (<i>MjHSD</i>) expression. MjHSD promoted lipid synthesis and restored lipid levels, thereby restricting viral replication. Importantly, pharmacological inhibition of lipid synthesis eliminated the antiviral effect of MjPvf2/MjPvr3 signaling. In conclusion, this study revealed the significance and mechanism of Pvf/Pvr signaling in antiviral immunity, providing novel insights into WSSV prevention and control in shrimp aquaculture.</p><p><strong>Importance: </strong>Viral infection affects host lipid metabolism. This process depletes the host's lipids to support viral replication. Pvf/Pvr signaling is widely involved in host physiological processes, but its role in viral infection has not been clarified. We demonstrate that Pvf/Pvr signaling exerts an antiviral effect by relieving the lipid consumption caused by white spot syndrome virus (WSSV) infection in shrimp. This study provides new insights into the effects of Pvf/Pvr signaling on antiviral immunity and highlights the complexity of lipid metabolism under WSSV infection.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0018226"},"PeriodicalIF":3.8,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775114","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":"The interaction between virus-bound KLF4 and host-bound PARP1 directs the localization of wild-type adeno-associated virus type 2 (wtAAV2) to cellular sites of DNA damage.","authors":"Rhiannon R Abrahams, Clairine I S Larsen, Raymond Ha, Kinjal Majumder","doi":"10.1128/jvi.00306-26","DOIUrl":"https://doi.org/10.1128/jvi.00306-26","url":null,"abstract":"<p><p>Wild-type adeno-associated virus type 2 (wtAAV2) is a small, non-pathogenic DNA virus within the family <i>Parvoviridae</i> that is modified to engineer recombinant AAV vectors used in gene therapy. wtAAV2 genomes localize to nuclear domains enriched in DNA damage response (DDR) factors through mechanisms that remain unknown. We have discovered that the host transcription factor KLF4 (Krüppel-like factor 4) and the DDR protein PARP1 (poly-ADP ribose polymerase 1) are key effectors regulating wtAAV2 nuclear trafficking. <i>In silico</i> analysis revealed that wtAAV2-associated genomic sites are enriched in KLF4 binding motifs. Confocal imaging demonstrated a close spatial association between KLF4 and wtAAV2 nuclear reservoirs, consistent with KLF4's known ability to form nuclear condensates. Mutation of the KLF4 binding site within the wtAAV2 genome and RNAi-mediated knockdown of KLF4 globally reduced the expression of viral <i>Rep68/78</i> genes and attenuated the localization of the viral genome to cellular DDR sites. Chemical inhibition of the KLF4-interacting protein PARP1 with olaparib decreased the ability of wtAAV2 genomes to localize to cellular DDR sites and transcribe viral genes. Ectopic expression of wild-type PARP1, but not its KLF4-binding-deficient mutant, rescued wtAAV2 gene expression in PARP1-deficient cells. These findings define a novel mechanism by which wtAAV2 exploits the interaction between host transcription factors and DNA repair machinery to establish a persistent nuclear niche. Insertion of KLF4-binding elements into recombinant AAV2 gene therapy vectors is sufficient to enhance transduction of target cells, providing a framework for engineering vectors with improved nuclear targeting and transcriptional activity.IMPORTANCEWild-type adeno-associated virus type 2 (wtAAV2) has emerged as the preferred platform for engineering gene therapy vectors due to its non-pathogenic nature and ability to persist in host cells long term. However, limited understanding of how wtAAV2 genomes navigate the nuclear environment to establish viral reservoirs has hindered the development of efficient recombinant AAV (rAAV) vectors. We demonstrate that the protein KLF4 bound to the wtAAV2 genome recruits the virus to cellular KLF4 sites bound by PARP1. Disruption of either KLF4 binding, PARP1 activity, or KLF4-PARP1 interaction significantly impairs wtAAV2 localization and transcription, highlighting the importance of their function in the non-replicative wtAAV2 life cycle. KLF4 binding sites are sufficient to improve the expression of transgenes from rAAV vectors and increase their association with cellular DNA damage response proteins. This study advances our understanding of wtAAV2-host interactions and opens new avenues for improving rAAV gene therapy platforms.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0030626"},"PeriodicalIF":3.8,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775237","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":"Effect of TAR hairpin stabilization on HIV-1 reverse transcription.","authors":"Sandra Da Silva Amaral, Clémence Richetta, Lola Oualid, Nhat Quang Tu, Brigitte René, Olivier Mauffret, Olivier Delelis, Philippe Fossé","doi":"10.1128/jvi.01840-25","DOIUrl":"https://doi.org/10.1128/jvi.01840-25","url":null,"abstract":"<p><p>Reverse transcription of the human immunodeficiency virus type 1 (HIV-1) genome requires the first strand transfer that relies on a base-pairing interaction between the 3' R sequence of the genomic RNA (gRNA) and the r sequence of the strong-stop DNA (ssDNA). The annealing reaction between the cTAR hairpin of ssDNA and the TAR hairpin of gRNA plays an essential role in r-3' R pairing. Studies suggest that HIV-1 nucleocapsid protein (NC) has only a minor role in ssDNA synthesis but facilitates the annealing reaction by destabilizing the two complementary hairpins. We designed mutations to increase the stability of the cTAR DNA hairpin. These mutations should impair the NC-mediated annealing process, but not other viral processes. We investigated the effects of mutations in the annealing reaction, viral infectivity, and reverse transcription in infected cells. The mutations stabilizing the lower stem of the cTAR hairpin impair the annealing reaction, strongly reduce HIV-1 replication, and the amount of full-length ssDNA in infected cells. The <i>in vitro</i> and <i>ex vivo</i> data support NC as the essential player in the first strand transfer reaction by facilitating the initiation of the cTAR-TAR pairing through the zipper pathway. These results agree with previous studies suggesting a coevolutionary relationship between the stability of the cTAR hairpin and NC activity. Our data are consistent with the hypothesis proposed in an early work, suggesting that ssDNA degradation by cellular nucleases occurs when the first strand transfer cannot take place. This attractive hypothesis warrants further investigation in future studies.IMPORTANCEThe first strand transfer is a crucial step of the reverse transcription process. Because the great majority of first strand transfers in HIV-1 occur with full-length ssDNA, the annealing reaction between the cTAR DNA hairpin and the 3' TAR RNA hairpin plays an essential role in the first strand transfer. To our knowledge, our study is the first to show that mutations stabilizing the lower stem of the cTAR hairpin strongly decrease the annealing reaction, HIV-1 replication, and the amount of full-length ssDNA in infected cells. Our data support the notion that NC is the essential player in the first strand transfer reaction by facilitating the initiation of the cTAR-TAR pairing through the zipper pathway.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0184025"},"PeriodicalIF":3.8,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775354","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":"Argininosuccinate synthase 1 (ASS1) orchestrates arginine metabolism and ornithine production to modulate CHIKV infection.","authors":"Nimisha Mishra, Mothe Sravya, Sonali Hanjankar, Anjali Singh, Yash Chaudhary, Ranjan Kumar Nanda, Sujatha Sunil","doi":"10.1128/jvi.02098-24","DOIUrl":"https://doi.org/10.1128/jvi.02098-24","url":null,"abstract":"<p><p>Viruses reprogram the host metabolic machinery to ensure a continuous supply of macromolecules and energy for their own survival. Important cellular pathways are impacted during infection, resulting in changes in key metabolic precursors that influence infection outcomes. The present study was undertaken to evaluate the impact of L-arginine and argininosuccinate synthase 1 (ASS1), an important upstream enzyme of the arginine metabolism pathway, during chikungunya virus (CHIKV) infection in the human liver-derived Huh-7 cells. Using dose-dependent and time-course L-arginine supplementation experiments, we demonstrated that CHIKV exploits cellular arginine for enhanced viral replication. Loss-of-function and gain-of-function studies of ASS1, combined with nitric oxide donor treatments, revealed that arginine metabolism influences multiple downstream pathways, including ornithine synthesis, proline metabolism, and nitric oxide production during CHIKV infection. We further examined the relationship between ASS1 expression and STAT3 signaling in the context of viral infection. Our results demonstrate that exogenous L-arginine supplementation and ASS1 overexpression enhance CHIKV replication in Huh-7 cells. Conversely, ASS1 silencing resulted in >95% reduction in viral titers. Mechanistically, ASS1 modulated arginase 1 activity, affecting ornithine production and downstream metabolites while also influencing the cellular nitroso-redox environment. Additionally, ASS1 expression affected STAT3 levels and its subcellular localization: ASS1 overexpression correlated with reduced nuclear STAT3 accumulation and increased viral replication, whereas ASS1 depletion promoted STAT3 nuclear translocation and restricted viral infection. These findings reveal a complex interplay between arginine metabolism, innate immune signaling, and CHIKV replication, identifying ASS1 as a potential regulatory node in CHIKV-host interactions.</p><p><strong>Importance: </strong>Metabolic reprogramming of the host is crucial for the virus to establish itself within the cell, and in this process, the virus hijacks several host metabolic pathways. We examined the role of an important arginine metabolizing enzyme, human argininosuccinate synthase (ASS1), during CHIKV infection in liver cells through silencing and overexpressing ASS1 and by L-arginine supplementation. We demonstrate that ASS1 favors CHIKV replication and also plays important roles in several downstream cellular processes during virus infection. This study further deepens our understanding of the significance of the crucial metabolites involved in the arginine metabolism pathway during CHIKV infection and how CHIKV exploits the specific pathway to enhance its replication.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0209824"},"PeriodicalIF":3.8,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775399","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":"A single residue in the VP3 capsid protein governs virulence and informs live-attenuated vaccine design for coxsackievirus A6.","authors":"Kexin Liu, Zeyu Liu, Xingyu Yan, Zhenlin Yang, Xue Li, Chao Zhang","doi":"10.1128/jvi.00149-26","DOIUrl":"https://doi.org/10.1128/jvi.00149-26","url":null,"abstract":"<p><p>Coxsackievirus A6 (CVA6) is a major pathogen of hand, foot, and mouth disease, yet the viral determinants of its severe pathogenicity remain undefined, hampering intervention strategies. Here, by comparing a highly lethal clinical isolate (CVA6-HeB) with an attenuated strain (CVA6-TW141), we identified the capsid-encoding P1 region as the primary virulence determinant in neonatal mice. Fine-mapping identified a single critical residue at position 238 of VP3 (VP3-238): glutamic acid (E) in virulent CVA6-HeB versus alanine (A) in attenuated CVA6-TW141. Introducing E238 into the attenuated CVA6-TW141 was sufficient to confer lethality, and conversely, reverting it to alanine in the lethal CVA6-HeB completely abolished virulence, demonstrating that VP3-E238 is necessary and sufficient for lethal disease. E238 is dominant (>93%) in circulating CVA6 strains, suggesting a significant fitness advantage. This residue is situated at the edge of the canyon, a key receptor-binding site. Replacing E238 with alanine (E238A) did not affect virion assembly or growth in cultured cells. However, this mutation drastically reduced binding to the essential murine entry receptor KREMEN1 and attenuated virulence by over 10,000-fold in mice, correlating with significantly lower tissue viral loads and pathology. Based on this mechanism, we rationally designed a live-attenuated vaccine candidate by introducing the attenuating E238A mutation. Immunization with this candidate provided complete protection against a subsequent lethal challenge with a heterologous CVA6 strain. Our study defines VP3-E238 as a key molecular switch for CVA6 pathogenicity and establishes a foundation for rational vaccine development.</p><p><strong>Importance: </strong>Hand, foot, and mouth disease is a common childhood illness increasingly caused by coxsackievirus A6 (CVA6), which can sometimes lead to severe complications. Currently, there are no specific vaccines or treatments available against CVA6. We identified the precise reason for the differing virulence between CVA6 strains. Comparing a lethal strain with a harmless one revealed a single determinant: residue 238 on the VP3 capsid protein. A glutamic acid (\"E\") at this site confers virulence, while alanine (\"A\") results in attenuation. By engineering an \"E\" to \"A\" mutation, we created a virus that is safe in mice but remains immunogenic. This engineered strain, used as a live vaccine, provided complete protection against lethal CVA6 challenge. Our work pinpoints a key virulence switch and presents a direct strategy for developing a safe CVA6 vaccine.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0014926"},"PeriodicalIF":3.8,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775424","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":"A novel replication-deficient feline herpesvirus type 1 vector-based vaccine provides strong immune protection in cats.","authors":"Wuchang Heng, Ziyan Zhou, Weiwei Lin, Xianglin Zhang, Ruibin Qi, Chenxi Wei, Qian Jiang, Hongtao Kang, Honglin Jia, Jiasen Liu","doi":"10.1128/jvi.02188-25","DOIUrl":"https://doi.org/10.1128/jvi.02188-25","url":null,"abstract":"<p><p>Feline herpesvirus type 1 (FHV-1) is a member of the Alphaherpesvirinae subfamily, which includes important pathogens affecting humans and animals, such as herpes simplex virus types 1 and 2, pseudorabies virus, and Marek's disease virus. While herpesviruses show promise as vaccine vectors for delivering foreign antigens, ensuring their safety is a significant concern that must be addressed alongside their efficacy. In this study, we report the development of a replication-defective FHV-1 ΔgL-based vaccine candidate, which is propagated exclusively in a specially modified F81 cell line. Vaccination of cats with the FHV-1 ΔgL-based candidate demonstrated a favorable safety profile and elicited protective immunity against FHV-1 challenge. More importantly, the FHV-1 ΔgL platform exhibits excellent efficacy in delivering the VP2 antigen of the feline panleukopenia virus (FPV), inducing high-titer neutralizing antibodies in cats. Furthermore, we evaluated a trivalent vaccine candidate, rQD1 ΔgL/gI/gE-VP2-VP1, in which an expression cassette for the feline calicivirus (FCV) VP1 was inserted to replace the gI/gE genes. Vaccination of cats with rQD1 ΔgL/gI/gE-VP2-VP1 produced a strong protective effect against challenges from FHV-1, FPV, and FCV. To support clinical manufacturing, we generated a stable cell line through site-specific integration of the gL gene into the Rosa26 safe-harbor locus of F81 cells. In conclusion, the FHV-1 ΔgL platform demonstrates safety, efficacy, and promising potential for future applications and serves as an example for constructing attenuated vaccines in alphaherpesviruses.IMPORTANCEHerpesviruses are highly effective at presenting foreign antigens and serve as excellent viral vectors, yet their safety warrants careful attention. We developed a replication-defective feline herpesvirus type 1 (FHV-1) ΔgL vector platform. Using this platform, a bivalent vaccine (rQD1 ΔgL-VP2) and a trivalent vaccine (rQD1 ΔgL/gI/gE-VP2-VP1) were constructed. Both vaccines demonstrated robust immunoprotection and favorable safety profiles in immunized cats. Furthermore, to facilitate the application of this platform, a stable cell line with site-specific integration, F81-gL-Rosa26, was generated by inserting the gL gene into the Rosa26 safe-harbor locus of F81 cells. The strategy of the FHV-1 ΔgL platform also provides a reference for other members of the herpesvirus family.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0218825"},"PeriodicalIF":3.8,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775436","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":"Predictive modeling of immune escape and antigenic grouping of SARS-CoV-2 variants.","authors":"Arshan Nasir, Diana Lee, Laura E Avena, Daniela Montes Berrueta, Tessa Speidel, Kai Wu, Yadunanda Budigi, Andrea Carfi, Guillaume B E Stewart-Jones, Darin Edwards","doi":"10.1128/jvi.00225-26","DOIUrl":"https://doi.org/10.1128/jvi.00225-26","url":null,"abstract":"<p><p>The ongoing adaptive evolution of Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is characterized by the continued emergence of variants with increased transmissibility and the ability to escape infection- and/or vaccine-induced immunity. This sustained antigenic evolution has necessitated updates to COVID-19 vaccine compositions to better match circulating viral variants. To optimize protection against emerging variants, a reliable means of predicting the immune escape of novel variants is needed to enable at-risk preparation of new vaccine strain compositions. Herein, we describe the development and applications of a quantitative risk calculator that predicts relative immune escape of SARS-CoV-2 variants using a statistical modeling framework. The approach integrates large-scale, experimentally derived spike-antibody epitope and escape maps with serum neutralization data generated using pseudotyped viruses and clinical sera. By aggregating site-level escape information into a strain-level metric, the calculator enables the grouping of antigenically related SARS-CoV-2 variants to guide strain selection for at-risk vaccine design and preparation, in anticipation of seasonal strain change recommendations by global public health agencies and the WHO. Here, we demonstrate the utility of this framework through retrospective and prospective strain selection exercises for the XBB.1.5-, JN.1/KP.2-, and LP.8.1-adapted mRNA-1273 COVID-19 vaccines during the 2023-2026 seasons, respectively. In all cases, model predictions were largely supported by clinical immunogenicity data and aligned with subsequent recommendations by global public health agencies.IMPORTANCEWe present a framework to estimate the relative immune escape potential of emerging variants by integrating previously published experimental epitope-level escape data with serum neutralization measurements. By consolidating mutation-level effects into a strain-level metric, this approach enables classification of antigenically similar variants. Retrospective and prospective applications demonstrate that model-based assessments are consistent with observed immunogenicity data. This framework provides a practical tool to support preparedness efforts by informing at-risk vaccine development activities in advance of seasonal strain selection guidance.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0022526"},"PeriodicalIF":3.8,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775061","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":"EV-D68 exploits clathrin-mediated endocytosis and compensatory macropinocytosis for cellular entry.","authors":"Chia-Yi Lin, Wen-Fang Tang, Kuang-Jing Huang, Li-Ting Wang, Jie-Yun Cai, Cheng-Hsun Chiu, Jim-Tong Horng","doi":"10.1128/jvi.00358-26","DOIUrl":"https://doi.org/10.1128/jvi.00358-26","url":null,"abstract":"<p><p>Despite growing health concerns about enterovirus D68 (EV-D68), its cellular entry mechanisms remain incompletely understood. In this study, we investigated the endocytic pathways exploited by the sialic acid-dependent EV-D68 TW-02795-2014 strain using pharmacological inhibitors, siRNA-mediated knockdown, dominant-negative constructs, and electron microscopic analysis. Chemical inhibition of clathrin-mediated endocytosis (CME), macropinocytosis, endosomal acidification, and other endocytic pathways reduced viral entry and protein expression, suggesting the involvement of multiple routes in viral entry. Co-localization of EV-D68 with clathrin and the effects of CME inhibitors supported CME as a major entry route. However, siRNA knockdown of CME components in RD cells inhibited the cellular uptake of transferrin, yet had no significant impact on EV-D68 infection. This was also seen in A549 cells. Notably, CME disruption by clathrin knockdown led to Rac1 upregulation and increased macropinocytosis, which facilitated EV-D68 entry. Transmission electron microscopy revealed membrane-associated EV-D68 particles organized in clusters underneath the cell surface during infection, potentially undergoing bulk internalization. In contrast, purified virions lacking membranous material strictly required CME for successful infection. These findings reveal a dual entry strategy: single (membrane-free) EV-D68 particles utilize CME, while membrane-associated virions access host cells via macropinocytosis, particularly under conditions of CME inhibition. This study highlights the complexity of EV-D68 endocytosis and underscores the importance of compensatory mechanisms in viral uptake.IMPORTANCEUnderstanding how EV-D68 enters host cells is crucial for developing antiviral strategies. This study uncovers a dual-entry mechanism used by a sialic acid-dependent EV-D68 strain: clathrin-mediated endocytosis (CME) for single virus particles, and macropinocytosis as an alternative route for membrane-associated particles or under conditions where CME is impaired. Notably, disruption of CME induces a compensatory upregulation of macropinocytosis, mediated by increased Rac1. These findings challenge prior assumptions of a singular viral entry pathway and emphasize the need to consider endocytic plasticity when designing antiviral interventions targeting EV-D68 or similar viruses.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0035826"},"PeriodicalIF":3.8,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147774586","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":"PTBP1 is upregulated in response to Zika virus infection and restrains viral replication by hijacking viral NS1 protein to induce NS1 degradation.","authors":"Menglan Rao, Yue Kong, Shuang Liu, Zicong Chen, Jiuxiu Lin, Yicong Liang, Zhiwei Lei, Zhen Luo","doi":"10.1128/jvi.01495-25","DOIUrl":"https://doi.org/10.1128/jvi.01495-25","url":null,"abstract":"<p><p>Zika virus (ZIKV), belonging to the <i>Flaviviridae</i> family, has been a severe threat to human health since the worldwide outbreak. ZIKV is capable of inducing fetal microcephaly, Guillain-Barré syndrome, and other serious neurological complications. Polypyrimidine tract-binding protein 1 (PTBP1) is a key member of the heterogeneous nuclear ribonucleoproteins (hnRNPs) family, functioning in selective mRNA splicing and gene expression regulation. Our previous study has indicated that the expression of PTBP1 increases in astrocytes upon ZIKV infection, yet the precise regulatory mechanisms underlying its role in viral replication remain elusive. In this study, we elucidated the specific pathway by which ZIKV upregulated PTBP1 expression through the activation of hypoxia-inducible factor-1α (HIF-1α) signal. Further investigation revealed that overexpression of PTBP1 effectively inhibited viral replication, whereas knockdown of PTBP1 significantly enhanced viral replication. Mechanistically, using co-immunoprecipitation assays for protein interaction screening, we identified an interaction between PTBP1 and ZIKV non-structural protein NS1. Detailed studies demonstrated that PTBP1 bound and colocalized with NS1 to lead to the degradation of NS1 protein via a lysosomal pathway. Collectively, our findings unveil a novel mechanism underlying that ZIKV infection induces the expression of PTBP1 via the HIF-1α pathway. Subsequently, the accumulated PTBP1 binds to the ZIKV NS1 protein, promoting NS1 degradation and thereby effectively inhibiting viral replication. The study illustrates a distinct restricted cellular factor that regulates ZIKV replication, which provides a potential target for the control of viral replication and pathogenesis during the ZIKV epidemic.IMPORTANCESince the outbreak of ZIKV infection among humans in 2014, a Zika epidemic has caused Zika fever accompanied by fetal microcephaly, Guillain-Barré syndrome, and other neurological symptoms. Emerging evidence reveals that ZIKV infects astrocytes to specifically induce the expression of polypyrimidine tract-binding protein 1 (PTBP1), one of the hnRNP members. However, the interplay between PTBP1 and ZIKV replication is unclear. Here, we uncover a distinct manner that ZIKV induces PTBP1 expression through the activation of hypoxia-inducible factor-1α (HIF-1α) signal. Additionally, activation of the HIF-1α signal hinders ZIKV replication, relying on PTBP1 accumulation. Further investigations suggest that PTBP1 restrains ZIKV replication by interacting with ZIKV NS1 protein, thereby leading to the degradation of NS1 protein via a lysosomal pathway. Collectively, our findings illustrate a novel restricted cellular factor PTBP1 mediated by HIF-1α that regulates ZIKV replication, which provides a potential therapeutic target of viral replication and pathogenesis against the ZIKV pandemic.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0149525"},"PeriodicalIF":3.8,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775132","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}