Journal of Virology最新文献

{"title":"Airway protease availability governs a reversible shift between syncytial and cell-free spread.","authors":"Joaquin Rodriguez Galvan, Maren de Vries, Shiraz Belblidia, Ashley Fisher, Meike Dittmann","doi":"10.1128/jvi.00727-26","DOIUrl":"10.1128/jvi.00727-26","url":null,"abstract":"<p><p>Paramyxoviruses such as respiratory syncytial virus (RSV) and human parainfluenza virus 3 (HPIV3) spread in the airway by releasing virions and by forming syncytia. Spread phenotypes are typically attributed to the fusion protein cleavage site, yet it remains unclear whether, and if so, how, host protease context biases syncytial versus cell-free spread. We compared RSV and HPIV3-two closely related viruses with overlapping epithelial tropism but distinct F cleavage-site composition (polybasic, furin-type for RSV versus a distinct, less polybasic cleavage-site motif for HPIV3)-in respiratory cell lines and primary airway cells under defined <i>in vitro</i> protease conditions. In multi-cycle infections, furin-dominant, trypsin-like-low environments produced the largest syncytia, whereas trypsin-like-high environments favored smaller syncytia and more cell-free spread. Adding exogenous TMPRSS2 shifted HPIV3 toward cell-free spread with minimal impact on RSV. Using serine protease inhibitors (SERPINs) as protease-selective inhibitors, we show that inhibiting specific proteases restricts infection and remodels syncytium architecture, consistent with protease switching. Together, these results indicate that host protease availability is a reversible control point for respiratory virus dissemination. This framework has direct implications for protease-targeting therapeutics. Selective inhibition may reroute fusion activation and shift spread modality toward more syncytia-associated cytopathic effects rather than uniformly suppressing dissemination.</p><p><strong>Importance: </strong>Respiratory syncytial virus and human parainfluenza virus 3 are leading causes of pneumonia and bronchiolitis in infants, the elderly, and immunocompromised patients, and disease severity tracks with how efficiently these viruses spread through the airway. Spread has long been attributed to a fixed feature of the viral fusion protein. Here, we show instead that the host airway environment-specifically, the proteases that activate viral fusion proteins-acts as a reversible switch between two modes of spread: virus release and cell-to-cell fusion. Because this switch can be moved, protease-targeting drugs may not simply block infection but redirect how the virus spreads, with consequences for tissue damage. Recognizing protease availability as a controllable determinant of dissemination reframes how we think about respiratory virus pathogenesis and offers a rationale for tuning, rather than only suppressing, viral spread with host-directed therapeutics.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0072726"},"PeriodicalIF":4.1,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148963504","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":"Interaction between DEAD-box RNA helicase 10 and influenza PB1 polymerase selectively regulates influenza A virus replication.","authors":"Rizwan Ullah, Wei Chen, Lingkai Zhang, Chaoxuan Guo, Bin Ren, Xinyi Pei, Dong Yang, Qingshuai Sun, Xinyu Gao, Hongbo Zhou, Liurong Fang, Wen Su","doi":"10.1128/jvi.00815-26","DOIUrl":"10.1128/jvi.00815-26","url":null,"abstract":"<p><p>Identifying the host factors that mediate avian influenza virus adaptation in mammals is important for monitoring zoonotic potential. Although viral polymerase adaptations are known to influence cross-species transmission, the engagement of specific host factors with divergent viral polymerases remains to be explored. We examined human DEAD-box RNA helicases (DDXs) as potential regulators of influenza polymerase activity. A screen of 16 DDXs identified DDX10 as a factor that selectively enhanced the polymerase activity and replication of human-adapted H1N1 viruses, including the 2009 pandemic strain, but not avian-origin H9N2 viruses. This differential activity was associated with DDX10 showing stronger interaction with human-origin PB1 (Cal04/H1N1) than with avian-origin PB1 (BJ16/H9N2). Strain specificity was mediated by two residues (336 and 364) within the PB1 catalytic domain: introducing H1N1-type residues (I336 and I364) into H9N2-PB1 conferred DDX10 responsiveness, while reciprocal mutations in H1N1-PB1 abolished it. This work defines DDX10 as a potential host factor that differentially supports influenza polymerase activity, revealing a specific molecular interface that contributes to the replication efficiency of distinct viral subtypes in human cells and providing insight into host-adaptive mechanisms.</p><p><strong>Importance: </strong>This study identifies DDX10 as a strain-specific host factor that differentially regulates influenza A virus replication. By demonstrating that DDX10 selectively enhances human-adapted H1N1 viruses over avian-origin H9N2 viruses through direct interaction with the viral PB1 protein, and by mapping two critical residues (positions 336 and 364) in PB1 that govern this selectivity, our work provides a mechanistic framework for understanding how a single host factor can modulate viral fitness and host adaptation. These findings have important implications for predicting cross-species transmission potential and may guide the development of host-targeted antiviral strategies.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0081526"},"PeriodicalIF":4.1,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149017141","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":"Deubiquitinase USP8 inhibits HIV-1 replication by suppressing Tat-mediated viral transactivation.","authors":"Jinsong Yuan, Weijing Yang, Mingxiu Xu, Haobo Hu, Shuhan Yang, Xiaodong Sun, Wenyan Zhang, Chen Huan","doi":"10.1128/jvi.00598-26","DOIUrl":"10.1128/jvi.00598-26","url":null,"abstract":"<p><p>Ubiquitin-specific proteases (USPs) modulate diverse virus-host interaction events through deubiquitination; thus, investigating their functional roles and molecular targets facilitates the interpretation of viral pathogenic mechanisms and informs the design of anti-virus strategies. The deubiquitinase USP8 has been reported to antagonize HIV-1 replication by reversing Vif-mediated ubiquitination of the host restriction factor A3G and shielding it from proteasomal degradation. Here, we identify an additional A3G-independent anti-HIV mechanism of USP8. In A3G-negative cells, USP8 exerts a potent inhibitory effect on HIV-1 replication by significantly suppressing viral transcription. Mechanistically, USP8 interacts with the HIV-1 trans-activator Tat through its C-terminal domain and mediates the removal of Tat's polyubiquitination chains in a manner dependent on USP8 catalytic activity. This disrupts the association between Tat and the HIV-1 LTR transactivation response (TAR) element, thus impairing Tat-mediated viral transactivation. Furthermore, given the essential role of Tat in driving viral gene expression, silencing of USP8 triggers latent HIV-1 reactivation. Collectively, our results, along with previous work, reveal that USP8 acts as a compelling anti-HIV factor that, by regulating both host and viral proteins, ultimately suppresses HIV-1 replication. These results deepen our understanding of USP8-mediated HIV-1 restriction and provide insights for the development of novel anti-HIV therapeutic strategies.IMPORTANCEUbiquitination modification contributes a non-negligible part to the regulation of HIV-1 replication, and the interpretation of key factors involved in this process has significantly benefited our understanding of the virus-host interplay. USP8 is a ubiquitin-specific protease that was recently identified to restrict HIV-1 replication by stabilizing the host restriction factor A3G through reversing the Vif-mediated ubiquitination of A3G. Here, we demonstrate an additional A3G-independent anti-HIV mechanism of USP8. In A3G-negative cells, USP8 directly interacts with and deubiquitinates Tat to cleave its K63-linked ubiquitination, thereby suppressing Tat-mediated HIV-1 trans-activation. The suppression of Tat-driven viral transcription induced by USP8 requires the enzymatic activity of USP8 and is effective in different HIV-1 tropic strains. In addition, the fact that Tat is a novel substrate of USP8 is validated both in cells and by <i>in vitro</i> deubiquitination assays. These findings illustrate the dual regulatory roles of USP8 on both host antiviral factors and viral proteins, expanding our understanding of host-mediated HIV-1 restriction.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0059826"},"PeriodicalIF":4.1,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149069893","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":"From viral infection to emission: host barriers shaping airborne transmission.","authors":"Patricia Romanos Martinez, Maximilian Rohde, Mohammad Yeasin, Saikat Basu, Christian Sieben, Julia R Port","doi":"10.1128/jvi.00753-26","DOIUrl":"10.1128/jvi.00753-26","url":null,"abstract":"<p><p>Coughing, speaking, and even quiet breathing can release virus-laden particles into the air, triggering transmission events that spread through households and communities. Understanding why some respiratory viruses transmit so efficiently, and under which biological or environmental conditions this occurs, is central to anticipating future outbreaks. In this review, we outline the biological and physical factors that shape respiratory virus transmission, highlighting how the site of replication, mechanisms of droplet generation, and environmental conditions influence airborne spread. We examine how viral traits such as receptor usage, tissue tropism, and innate immune evasion intersect with airway physiology to determine the size, composition, and infectiousness of exhaled particles. We lastly draw attention to key gaps in current knowledge, particularly regarding the host and environmental factors that govern both the release and uptake of virions. Filling these gaps will allow us to more accurately assess transmission risk and implement targeted approaches to reduce spread.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0075326"},"PeriodicalIF":4.1,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149069896","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":"Expanded protocadherin-1 usage reveals a broader hantavirus entry landscape.","authors":"Cierra Word, Nahomi Guerra-Pilaquinga, Ezgi Kasikci, Lohit Khera, Ramandeep Kaur, Upendra P Lambe, Alexis Ortega, Maria Eugenia Dieterle, Kartik Chandran, Rohit K Jangra","doi":"10.1128/jvi.00994-26","DOIUrl":"10.1128/jvi.00994-26","url":null,"abstract":"<p><p>Mammalian hantaviruses are RNA viruses that cause hantavirus cardiopulmonary syndrome in the Americas and hemorrhagic fever with renal syndrome in Eurasia. The cellular entry mechanisms of most hantaviruses remain poorly defined. To examine entry by phylogenetically distinct hantaviruses identified across Africa, Eurasia, and the Americas, we generated replication-competent recombinant vesicular stomatitis viruses (rVSVs) bearing Gn/Gc proteins from Necoclí, Sangassou, Thottapalayam, Kenkeme, Nova, Oxbow, and Tula viruses. All these Gn/Gc proteins except Kenkeme supported infection of primary human endothelial cells, indicating that endothelial cell entry is permissive for a broader range of hantaviruses than previously appreciated. Except for rVSV-Kenkeme, these rVSVs did not acquire additional mutations beyond pre-engineered rescue-enhancing changes during rescue and passaging. Genetic studies in human cells lacking protocadherin-1 (PCDH1) showed that Necoclí, Tula, and Nova viruses use PCDH1 for efficient infection, although the Nova phenotype was weaker. These three Gn/Gc proteins bound soluble PCDH1 with different apparent avidities, and infection by the corresponding rVSVs was inhibited by soluble PCDH1; Necoclí and Tula, but not Nova, were also blocked by a PCDH1-targeting monoclonal antibody. Authentic Tula virus infection was similarly reduced in PCDH1 knockout endothelial cells. Finally, the broadly reactive anti-Gn/Gc human monoclonal antibody ADI-42898 efficiently neutralized Necoclí, Nova, Sangassou, and Kenkeme rVSVs, but showed weak or undetectable activity against Oxbow, Tula, and Thottapalayam rVSVs. Together, these findings expand the range of hantavirus glycoproteins capable of mediating infection of human endothelial cells, broaden the phylogenetic scope of PCDH1-dependent entry, and identify receptor-targeted and viral glycoprotein-targeted strategies with differential activity.IMPORTANCEMany newly discovered hantaviruses are known only from sequence data, leaving their ability to enter human cells and their receptor usage unresolved. Using a BSL2-compatible recombinant vesicular stomatitis virus (rVSV) system, we show that glycoproteins from several divergent hantaviruses can mediate infection of primary human endothelial cells, indicating that endothelial cell entry is permissive for a broader range of hantaviruses than previously appreciated. We also show that protocadherin-1 (PCDH1), previously linked mainly to New World hantaviruses, is used by Necoclí, Tula, and Nova viruses but not universally across the panel, revealing broader but heterogeneous receptor usage. An authentic Tula virus experiment supports this conclusion beyond the surrogate system. Finally, a broadly reactive anti-Gn/Gc antibody neutralizes several, but not all, of these viruses, highlighting both the promise and the limits of broadly protective countermeasures and the utility of these rVSVs for evaluating entry inhibitors.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0099426"},"PeriodicalIF":4.1,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075073","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":"Broadly reactive antibodies against influenza B virus hemagglutinin neutralize and protect through distinct structural mechanisms.","authors":"Disha Bhavsar, Alesandro Civljak, Bruno Bonnettaz, Guha Asthagiri Arunkumar, Florian Krammer, Goran Bajic","doi":"10.1128/jvi.00802-26","DOIUrl":"10.1128/jvi.00802-26","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Influenza B viruses contribute substantially to seasonal disease burden; however, the structural basis by which antibodies recognize the major glycoprotein hemagglutinin (HA) and mediate antiviral activity remains incompletely defined. Influenza B virus used to circulate as two antigenically distinct lineages, B/Victoria/2/1987-like and B/Yamagata/16/1988-like, although the latter has not been detected in global surveillance in recent years. Antigenic drift in HA contributes to reduced vaccine effectiveness; however, the structural and functional basis by which antibodies recognize influenza B virus HA and mediate antiviral activity remains incompletely defined and thus thwarts our efforts in guiding next-generation vaccine design for broad protection. We characterize four murine monoclonal antibodies (mAb) that broadly bind and neutralize influenza B viruses spanning isolates across four decades of antigenic drift. Using cryo-electron microscopy coupled with &lt;i&gt;in vitro&lt;/i&gt; and &lt;i&gt;in vivo&lt;/i&gt; functional assays, we show that these antibodies target distinct regions of HA and confer antiviral activity through multiple mechanisms. One antibody engages the receptor-binding site and potently inhibits hemagglutination, whereas others interfere with viral egress and inhibit neuraminidase (NA) activity, suggesting steric occlusion of NA. A medial-junction antibody additionally induces antibody-dependent cellular cytotoxicity &lt;i&gt;in vitro&lt;/i&gt;. Despite these mechanistic differences, all antibodies confer complete protection in mice when administered prophylactically or therapeutically. Together, these findings define distinct modes of antibody recognition of influenza B virus HA and link epitope specificity to antiviral function, providing a mechanistic understanding of correlates of immune protection and informing efforts to elicit broadly protective antibody responses against influenza B viruses.IMPORTANCEInfluenza B viruses cause substantial seasonal illness, particularly in children; however, antibody responses against influenza B virus remain less well understood than those against influenza A virus. Here, we identified four antibodies that broadly recognize influenza B virus hemagglutinin and protect through distinct mechanisms. We determined cryo-electron microscopy structures of three antibody-hemagglutinin complexes to define their epitopes and explain their molecular mechanisms of action. One antibody blocks viral attachment by engaging the receptor-binding site, whereas antibodies targeting the medial junction act through post-entry antiviral activity, neuraminidase inhibition, or immune effector functions. Although the antibodies differed in neutralizing potency, all protected mice when administered before infection, and several remained effective after infection. These findings show that broad protection against influenza B virus can arise through multiple antibody targets and mechanisms, informing the evaluation and design of future vac","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0080226"},"PeriodicalIF":4.1,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148892184","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":"Interferome profiling in the blood links IFNα5-Mucin-1 axis to HIV-1 pathogenesis.","authors":"Kejun Guo, Stephanie M Dillon, Emily C Meneses, Bradley S Barrett, Alexandra Norman, Kaylee L Mickens, James H Morrison, Ulf Dittmer, Kathrin Sutter, Eric M Poeschla, Katerina Kechris, Cara C Wilson, Mario L Santiago","doi":"10.1128/jvi.01089-26","DOIUrl":"10.1128/jvi.01089-26","url":null,"abstract":"<p><p>Type I interferons (IFN-Is) are essential for antiviral immunity, but contribute to immune dysfunction during chronic HIV-1 infection. IFN-Is comprise multiple IFNα subtypes that signal through a common receptor yet exhibit distinct biological activities, but their qualitative roles in HIV-1 pathogenesis remain incompletely defined. We previously identified IFNα5 as the dominant IFN-I in the systemic circulation of untreated people with HIV (PWH). Here, we delineated IFNα subtype-specific interferomes in peripheral blood mononuclear cells (PBMCs) from HIV-uninfected donors by transcriptomic profiling, and integrated these signatures with blood transcriptomes from untreated PWH, and matched controls. Although the IFN-Is tested induced canonical interferon-stimulated genes (ISGs) <i>in vitro</i>, they also induced different transcriptional programs. <i>In vivo</i>, dysregulation of multiple canonical ISGs, including <i>CD38</i>, <i>LAG3</i>, and <i>CMPK2</i>, correlated with plasma HIV-1 RNA levels, CD4 T-cell depletion, and/or systemic inflammatory markers. By contrast, the IFN-downregulated genes <i>CXCL5</i> and <i>VSIG4</i> were repressed in PWH and inversely correlated with viral load. Notably, <i>MUC1</i>, a non-canonical ISG that was most strongly induced by IFNα5, was significantly upregulated in PWH and associated with the inhibitory receptor <i>LAG3</i>, and markers of IL-6-driven inflammation. Flow cytometric analysis demonstrated increased Mucin-1 surface density on circulating CD4 T cells of PWH vs controls. Together, these findings demonstrate that IFNα subtypes can drive qualitatively distinct responses in bulk PBMC, identify IFNα5-associated gene programs in blood that may contribute to immune dysregulation among untreated PWH, and refine current models of IFN-I involvement in HIV-1 pathogenesis.IMPORTANCEPeople living with HIV experience persistent immune activation and inflammation that contribute to immune system damage and long-term health complications. Molecules known as type I interferons (IFN-Is) help control viruses early in infection, but prolonged exposure to these signals may also worsen immune dysfunction. Here, we show that IFNα5 is the dominant interferon present in the blood of people with untreated HIV and activates a distinct gene program in circulating immune cells. This program includes genes linked to immune activation, metabolic dysfunction, and immune exhaustion. IFNα5 strongly induces Mucin-1 on CD4 T cells, which is associated with systemic inflammation. These findings identify IFN pathways that may contribute to immune dysfunction during chronic HIV infection and highlight potential targets for restoring immune health.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0108926"},"PeriodicalIF":4.1,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149039543","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":"Virus-specific T cells and neutralizing antibodies are independent correlates of long-term protective immunity against hepatitis C virus.","authors":"Elsa Gomez-Escobar, Asiyah Siddique, Omar Khedr, Nathalie Bédard, Alizée Fieffé-Bédard, Nourtan F Abdeltawab, Nicol Flores, Mohamed S Abdel-Hakeem, Mohamed Eisa, Geng Zang, John Lok Man Law, Juthika Kundu, Michael Houghton, Julie Bruneau, Naglaa H Shoukry","doi":"10.1128/jvi.00849-26","DOIUrl":"10.1128/jvi.00849-26","url":null,"abstract":"<p><p>Virus-specific T cells and broadly neutralizing antibodies (NAbs) are associated with spontaneous clearance of acute primary hepatitis C virus (HCV) infection and reinfection. Following spontaneous clearance, HCV-specific memory T cells are long-lived, but NAbs are less durable. How these two arms contribute to long-term protective immunity upon re-exposure is unknown. Herein, we compared the magnitude and breadth of memory HCV-specific T cells and NAbs in a cohort of HCV-spontaneously resolved people who inject drugs with high-risk exposure to the virus but who remained free of observed reinfections (FOR, <i>n</i> = 34) or who got reinfected (<i>n</i> = 22). Among FOR, 73.5% (<i>n</i> = 25) exhibited high frequencies of gamma interferon (IFN-γ)-producing T cells, while 23.5% (<i>n</i> = 8) showed high neutralization breadth (>25% neutralization of HCV pseudoparticles [HCVpp]) and/or potency (geometric mean neutralization >50% against seven HCVpp). Notably, some subjects had detectable NAbs several years after clearance. Multivariate random forest analysis demonstrated that the frequency of IFN-γ-producing T cells and the NAb response against only one difficult-to-neutralize HCVpp (1b58) were significant predictors of protection against reinfection (<i>P</i> < 0.05). Longitudinal analysis of the immune response in subjects with multiple episodes of infection showed that strong and broad HCV-specific T cell responses were associated with spontaneously cleared episodes. In contrast, NAbs did not protect from chronicity upon re-exposure in the absence of memory T cells, or if they were unable to recognize the infecting virus due to imprinting by strains of the previous episodes. In conclusion, T cell responses and NAbs targeting specific isolates are independent predictors of long-term protective immunity against HCV.</p><p><strong>Importance: </strong>Hepatitis C virus (HCV) is a blood-borne virus that disproportionately affects people who inject drugs. Most HCV infections become persistent, leading to liver fibrosis and cancer. Although effective antiviral therapies are available, around 50 million people remain persistently infected with HCV and can transmit the virus. Currently, there is no available vaccine to control the spread of HCV. However, around one in four people infected can naturally clear the virus, becoming partially protected upon re-exposure, suggesting it is possible to develop a vaccine that induces similar protection. In this study, we investigated the contribution of T cells and neutralizing antibodies to protection against observed reinfection in a cohort of people who inject drugs and have naturally cleared HCV, yet remain at high-risk exposure. Our findings suggest that strong T cell responses and neutralizing antibodies targeting hard-to-neutralize isolates could predict protective immunity upon reinfection.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0084926"},"PeriodicalIF":4.1,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148920210","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 multi-pronged entry of African swine fever virus: from host factors to therapeutic targets.","authors":"Jiaqi Li, Chuanxia Liu, Weitao Huang, Yibing Wang, Li Huang, Changjiang Weng","doi":"10.1128/jvi.00924-26","DOIUrl":"10.1128/jvi.00924-26","url":null,"abstract":"<p><p>African swine fever (ASF), caused by the African swine fever virus (ASFV), remains one of the most devastating transboundary animal diseases worldwide, with case fatality rates reaching up to 100% in acute infections. Viral entry represents the first essential step in infection and is an ideal target for the development of vaccines and antiviral drugs. Recent studies have revealed that ASFV entry is not mediated by a single receptor or pathway. Instead, it involves multiple viral structural proteins, cellular attachment factors, endocytic routes, and intracellular trafficking regulators, which form a coordinated virus-host interaction network. In this review, we systematically summarize recent advances in ASFV multi-pathway invasion, including viral attachment, internalization, intracellular trafficking, uncoating, and membrane fusion. Additionally, we discuss several unresolved questions and highlight promising antiviral and genetic intervention strategies that target both viral components and host determinants. A comprehensive understanding of ASFV entry will provide the theoretical foundation for developing next-generation vaccines, antivirals, and disease-resistant pig populations.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0092426"},"PeriodicalIF":4.1,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149025285","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":"Rift Valley fever virus virulence factor NSs targets ATF4- and XBP1-driven unfolded protein response.","authors":"Kaori Terasaki, Shinji Makino","doi":"10.1128/jvi.01233-26","DOIUrl":"10.1128/jvi.01233-26","url":null,"abstract":"<p><p>Rift Valley fever virus (RVFV) is a mosquito-borne arbovirus that infects humans and domestic ruminants, significantly impacting public health and the economy in African and Middle Eastern countries. RVFV non-structural protein NSs is a major viral virulence factor and possesses multiple functions to counteract host antiviral responses. One of its functions is to block host transcription by promoting degradation of subunits of the host transcription factor IIH (TFIIH). However, the biological significance of this function in the RVFV life cycle remains unclear. We used RVFV strain MP-12 and its mutant lacking the TFIIH degradation function (NSs-mut virus) to identify host genes targeted by NSs-mediated transcription suppression. We found that NSs-mut virus, but not MP-12, upregulated unfolded protein response (UPR) target genes compared to uninfected cells. Both viruses activated all three ER stress sensors, including PERK and IRE1. However, only MP-12 inhibited the PERK and IRE1 pathways by inhibiting the expression of their respective downstream mediators ATF4 and XBP1. ATF4 expression was inhibited at the transcriptional level, whereas XBP1 expression was inhibited at the post-transcriptional level. ATF4 depletion negatively impacted virus titer and the production of non-plaque-forming particles, resulting in alteration of the particle-to-PFU ratio of the viruses. We also showed that activation of the PERK pathway plays a pro-survival role in NSs-mut virus-infected cells, suggesting the involvement of the PERK pathway in RVFV-induced cytotoxicity. Taken together, our study revealed that RVFV NSs inhibits two out of the three UPR pathways and promotes RVFV-induced cytotoxicity by inhibiting the PERK pathway.IMPORTANCEThe Rift Valley fever virus (RVFV) NSs protein is a major virulence factor with multiple functions, including inhibition of general host transcription. RVFV carrying a mutated NSs that lacks the transcription suppression function is less cytotoxic <i>in vitro</i> and less virulent in mice compared to its parental virus, suggesting that NSs-mediated host transcription suppression is important for RVFV virulence. Experiments using this mutant virus and its parental RVFV revealed that NSs inhibits the expression of unfolded protein response (UPR) mediators ATF4 and XBP1, which act downstream of the PERK and IRE1 pathways, respectively. Our data also showed that activation of PERK promotes cell survival in RVFV infection. These data suggest that the NSs-mediated inhibition of UPR pathways contributes to RVFV pathogenicity.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0123326"},"PeriodicalIF":4.1,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149039552","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}