Journal of Virology最新文献

{"title":"Studying bats using a One Health lens: bridging the gap between bat virology and disease ecology.","authors":"Victoria Gonzalez, Arianna M Hurtado-Monzón, Sabrina O'Krafka, Elke Mühlberger, Michael Letko, Hannah K Frank, Eric D Laing, Kendra L Phelps, Daniel J Becker, Vincent J Munster, Darryl Falzarano, Tony Schountz, Stephanie N Seifert, Arinjay Banerjee","doi":"10.1128/jvi.01453-24","DOIUrl":"10.1128/jvi.01453-24","url":null,"abstract":"<p><p>Accumulating data suggest that some bat species host emerging viruses that are highly pathogenic in humans and agricultural animals. Laboratory-based studies have highlighted important adaptations in bat immune systems that allow them to better tolerate viral infections compared to humans. Simultaneously, ecological studies have discovered critical extrinsic factors, such as nutritional stress, that correlate with virus shedding in wild-caught bats. Despite some progress in independently understanding the role of bats as reservoirs of emerging viruses, there remains a significant gap in the molecular understanding of factors that drive virus spillover from bats. Driven by a collective goal of bridging the gap between the fields of bat virology, immunology, and disease ecology, we hosted a satellite symposium at the 2024 American Society for Virology meeting. Bringing together virologists, immunologists, and disease ecologists, we discussed the intrinsic and extrinsic factors such as virus receptor engagement, adaptive immunity, and virus ecology that influence spillover from bat hosts. This article summarizes the topics discussed during the symposium and emphasizes the need for interdisciplinary collaborations and resource sharing.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0145324"},"PeriodicalIF":4.0,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11650978/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of the critical residues of TMPRSS2 for entry and host range of human coronavirus HKU1.","authors":"Yahan Chen, Xiuyuan Ou, Pei Li, Fuwen Zan, Lin Tan, Zhaohui Qian","doi":"10.1128/jvi.01587-24","DOIUrl":"10.1128/jvi.01587-24","url":null,"abstract":"<p><p>Human coronavirus (CoV) HKU1 infection typically causes common cold but can lead to pneumonia in children, older people, and immunosuppressed individuals. Recently, human transmembrane serine protease 2 (hTMPRSS2) was identified as the functional receptor for HKU1, but its region and residues critical for HKU1 S binding remain elusive. In this study, we find that HKU1 could utilize human and hamster, but not rat, mouse, or bat TMPRSS2 for virus entry, displaying a narrow host range. Using human-bat TMPRSS2 chimeras, we show that the serine peptidase (SP) domain of TMPRSS2 is essential for entry of HKU1. Further extensive mutagenesis analyses of the C-terminal regions of SP domains of human and bat TMPRSS2s identify residues 417 and 469 critical for entry of HKU1. Replacement of either D417 or Y469 with asparagine in hTMPRSS2 abolishes its abilities to mediate entry of HKU1 S pseudovirions and cell-cell fusion, whereas substitution of N417 with D or N469 with Y in bat TMPRSS2 (bTMPRSS2) renders it supporting HKU1 entry. Our findings contribute to a deeper understanding of coronavirus-receptor interactions and cross-species transmission.IMPORTANCEThe interactions of coronavirus (CoV) S proteins with their cognate receptors determine the host range and cross-species transmission potential. Recently, human transmembrane serine protease 2 (hTMPRSS2) was found to be the receptor for HKU1. Here, we show that the TMPRSS2 of hamster, but not rat, mouse, or bat, can serve as a functional entry receptor for HKU1. Moreover, swapping the residues at the positions of 417 and 469 of bTMPRSS2 with the corresponding residues of hTMPRSS2 confers it supporting entry of HKU1 S pseudovirions, indicating the critical role of these residues in HKU1 entry. Our study identified the critical residues in hTMPRSS2 responsible for receptor interaction and host range of HKU1.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0158724"},"PeriodicalIF":4.0,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11650973/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142622739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantifying the impact of vaccination on transmission and diversity of influenza A variants in pigs.","authors":"Chong Li, Marie R Culhane, Declan C Schroeder, Maxim C-J Cheeran, Lucina Galina Pantoja, Micah L Jansen, Montserrat Torremorell","doi":"10.1128/jvi.01245-24","DOIUrl":"10.1128/jvi.01245-24","url":null,"abstract":"<p><p>Global evolutionary dynamics of influenza A virus (IAV) are fundamentally driven by the extent of virus diversity generated, transmitted, and shaped in individual hosts. How vaccination affects the degree of IAV genetic diversity that can be transmitted and expanded in pigs is unknown. To evaluate the effect of vaccination on the transmission of genetically distinct IAV variants and their diversity after transmission in pigs, we examined the whole genome of IAV recovered from the nasal cavities of pigs vaccinated with different influenza immunization regimens after being infected simultaneously by H1N1 and H3N2 IAVs using a seeder pig model. We found that the seeder pigs harbored more diversified virus populations than the contact pigs. Among contact pigs, H3N2 and H1N1 viruses recovered from pigs vaccinated with a single dose of an unmatched modified live vaccine generally accumulated more extensive genetic mutations than non-vaccinated pigs. Furthermore, the non-sterilizing immunity elicited by the single-dose-modified live vaccine may have exerted positive selection on H1 antigenic regions as we detected significantly higher nonsynonymous but lower synonymous evolutionary rates in H1 antigenic regions than non-antigenic regions. In addition, we observed that the vaccinated pigs shared significantly less proportion of H3N2 variants with seeder pigs than unvaccinated pigs. These results indicated that vaccination might reduce the impact of transmitted influenza variants on the overall diversity of IAV populations harbored in recipient pigs and that within-host genetic selection of IAV is more likely to occur in pigs vaccinated with improperly matched vaccines.IMPORTANCEUnderstanding how vaccination shapes the diversity of influenza variants that transmit and propagate among pigs is essential for designing effective IAV surveillance and control programs. Current knowledge about the transmission of IAV variants has primarily been explored in humans during natural infection. However, how immunity elicited by improperly matched vaccines affects the degree of IAV genetic diversity that can be transmitted and expanded in pigs at the whole-genome level is unknown. We analyzed IAV sequences from samples collected daily from experimentally infected pigs vaccinated with various protocols in a field-represented IAV co-infection model. We found that vaccine-induced non-sterilizing immunity might promote genetic variation on the IAV genome and drive positive selection at antigenic sites during infection. In addition, a smaller proportion of H3N2 viral variants were shared between seeder pigs and vaccinated pigs, suggesting the influence of vaccination on shaping the virus genomic diversity in recipient pigs during the transmission events.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0124524"},"PeriodicalIF":4.0,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11651001/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142622800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autophagy promotes p72 degradation and capsid disassembly during the early phase of African swine fever virus infection.","authors":"Jie Song, Jiangnan Li, Shuai Li, Gaihong Zhao, Tingting Li, Xin Chen, Boli Hu, Jia Liu, Xinyu Lai, Sitong Liu, Qiongqiong Zhou, Li Huang, Changjiang Weng","doi":"10.1128/jvi.01701-24","DOIUrl":"https://doi.org/10.1128/jvi.01701-24","url":null,"abstract":"<p><p>During viral infections, autophagy functions as a cell-intrinsic defense mechanism by facilitating the delivery of virions or viral components to the endosomal/lysosomal pathway for degradation. In this study, we report that internalized African swine fever virus (ASFV) virions enter autolysosomes during the early phase of viral infection. Autophagy selectively targets the major capsid protein p72 within the ASFV virion. The ASFV p72 protein undergoes modification through ubiquitination at the C-terminus, a process mediated by the E3 ubiquitin ligase Stub1. Subsequently, ubiquitinated p72 is recognized by the autophagy receptor SQSTM1/p62 through its ubiquitin-binding domain. Stub1 facilitates the ubiquitination and degradation of p72 in an HSPA8-dependent manner <i>via</i> selective autophagy. Autophagy plays a critical role in disassembling ASFV virions and further promotes the release of ASFV genomic DNA. These findings support the notion that autophagy is involved in and contributes to the capsid disassembly of ASFV, providing valuable insights into this essential viral process.IMPORTANCEAfrican swine fever (ASF), a highly contagious disease caused by the ASF virus (ASFV), affects domestic pigs and wild boars, with a mortality rate of up to 100%. The ASF epidemic poses a persistent threat to the global pig industry. Currently, no effective vaccines or antiviral drugs are available for prevention and control. In this study, we discovered that autophagy promotes the degradation of p72 and the disassembly of the capsid during the early phase of ASFV infection. Mechanically, Stub1 facilitates the polyubiquitination of ASFV p72 through the chaperone HSPA8. The polyubiquitinated p72 then interacts with the autophagy receptor SQSTM1/p62, leading to its degradation <i>via</i> the selective autophagy pathway. These findings reveal the mechanism of p72 degradation through autophagy and provide new insights into the capsid disassembly process of ASFV.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0170124"},"PeriodicalIF":4.0,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142837327","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":"Visualizing the virus world inside the cell by cryo-electron tomography.","authors":"Qunfei Zhou, Shee-Mei Lok","doi":"10.1128/jvi.01085-23","DOIUrl":"10.1128/jvi.01085-23","url":null,"abstract":"<p><p>Structural studies on purified virus have revealed intricate architectures, but there is little structural information on how viruses interact with host cells <i>in situ</i>. Cryo-focused ion beam (FIB) milling and cryo-electron tomography (cryo-ET) have emerged as revolutionary tools in structural biology to visualize the dynamic conformational of viral particles and their interactions with host factors within infected cells. Here, we review the state-of-the-art cryo-ET technique for <i>in situ</i> viral structure studies and highlight exemplary studies that showcase the remarkable capabilities of cryo-ET in capturing the dynamic virus-host interaction, advancing our understanding of viral infection and pathogenesis.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0108523"},"PeriodicalIF":4.0,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11650999/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction for Liang et al., \"Chicken or Porcine Aminopeptidase N Mediates Cellular Entry of Pseudoviruses Carrying Spike Glycoprotein from the Avian Deltacoronaviruses HKU11, HKU13, and HKU17\".","authors":"Qi-Zhang Liang, Bin Wang, Chun-Miao Ji, Feifan Hu, Pan Qin, Yaoyu Feng, Yan-Dong Tang, Yao-Wei Huang","doi":"10.1128/jvi.01631-24","DOIUrl":"10.1128/jvi.01631-24","url":null,"abstract":"","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0163124"},"PeriodicalIF":4.0,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11650966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The herpes simplex virus alkaline nuclease is required to maintain replication fork progression.","authors":"Patrick J Mullon, Emiliano Maldonado-Luevano, Kavi P M Mehta, Kareem N Mohni","doi":"10.1128/jvi.01836-24","DOIUrl":"10.1128/jvi.01836-24","url":null,"abstract":"<p><p>Herpes simplex virus is a large double-strand DNA virus that replicates in the nucleus of the host cell and interacts with host DNA replication and repair proteins. The viral 5' to 3' alkaline nuclease, UL12, is required for production of DNA that can be packaged into infectious virus. The UL12-deleted virus, AN-1, exhibits near wild-type levels of viral DNA replication, but the DNA cannot be packaged into capsids, suggesting it is structurally aberrant. To better understand the DNA replication defect observed in AN-1, we utilized isolation of proteins on nascent DNA (iPOND), a powerful tool to study all the proteins at a DNA replication fork. Combining iPOND with stable isotope labeling of amino acids in cell culture (SILAC) allows for a quantitative assessment of protein abundance when comparing wild type to mutant replication forks. We performed five replicates of iPOND-SILAC comparing AN-1 to the wild-type virus, KOS. We observed 60 proteins that were significantly lost from AN-1 forks out of over 1,000 quantified proteins. These proteins largely represent host DNA replication proteins including MCM2-7, RFC1-5, MSH2/6, MRN, and proliferating cell nuclear antigen. These observations are reminiscent of how these proteins behave at stalled human replication forks. We also observed similar protein changes when we stalled KOS forks with hydroxyurea. Additionally, we observed a decrease in the rate of AN-1 replication fork progression at the single-molecule level. These data indicate that UL12 is required for DNA replication fork progression and that forks stall in the absence of UL12.</p><p><strong>Importance: </strong>Herpes simplex virus 1 (HSV-1) is a near-ubiquitous pathogen within the global population, causing a lifelong latent infection with sporadic reactivation throughout the life of the host. Within at-risk and immunocompromised communities, HSV-1 infection can cause serious morbidities including herpes keratitis and encephalitis. With the possibility of herpesviruses to evade established antiviral therapies and there being no approved HSV-1 vaccine, there comes a need to investigate potential targets for intervention against infection and subsequent disease. UL12 is the viral 5'-3' exonuclease, which is required for the production of infectious progeny. In this study, we show that in the absence of UL12, viral replication fork progression is abrogated. These data point to UL12 as an attractive target for intervention, which could lead to better clinical outcomes of HSV-1-associated disease in the future.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0183624"},"PeriodicalIF":4.0,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11650972/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vaccine candidates based on MVA viral vectors expressing VP2 or VP7 confer full protection against Epizootic hemorrhagic disease virus in IFNAR(-/-) mice.","authors":"Luis Jiménez-Cabello, Sergio Utrilla-Trigo, Karen Rodríguez-Sabando, Alejandro Carra-Valenzuela, Miguel Illescas-Amo, Eva Calvo-Pinilla, Javier Ortego","doi":"10.1128/jvi.01687-24","DOIUrl":"10.1128/jvi.01687-24","url":null,"abstract":"<p><p>Epizootic hemorrhagic disease (EHD), caused by Epizootic hemorrhagic disease virus (EHDV), is an emerging and severe livestock disease. Recent incursion and distribution of EHDV in Europe have outlined the need for vaccine research against this viral disease. In this work, we report modified vaccinia virus Ankara (MVA)-vectored vaccines designed to express protein VP2 of EHDV-8 or protein VP7 of EHDV-2. Prime boost immunization of adult IFNAR(-/-) mice with the MVA-VP2 vaccine candidate induced high titers of EHDV-8-specific neutralizing antibodies (NAbs) and conferred full protection against homologous lethal challenge with EHDV-8. However, no heterologous protection was observed after lethal challenge with EHDV-6. In contrast, the MVA-VP7 vaccine candidate elicited strong cytotoxic CD8+ T-cell responses against VP7 and conferred complete protection against lethal challenge with either EHDV-8 or EHDV-6 in IFNAR(-/-) mice in the absence of NAbs, being the first multiserotype vaccine candidate against EHDV. Moreover, we expressed recombinant proteins VP2 and VP7 of EHDV in the baculovirus expression system, which were used to analyze the potential DIVA (differentiating infected from vaccinated animals) character of these vaccine candidates.IMPORTANCEEmergence and re-emergence of arthropod-borne viruses are major concerns for both human and animal health. The most recent example is the fast expansion of EHDV-8 through Europe. Besides, EHDV-8 relates with a high prevalence of pathologic cases in cattle populations. No vaccine is currently available in Europe, and vaccine research against this arboviral disease is negligible. In this work, we present novel DIVA vaccine candidates against EHDV, and most importantly, we identified the protein VP7 of EHDV as an antigen capable of inducing multiserotype protection, one of the major challenges in vaccine research against orbiviruses.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0168724"},"PeriodicalIF":4.0,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11650994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inactivation of checkpoint kinase 1 (Chk1) during parvovirus minute virus of mice (MVM) infection inhibits cellular homologous recombination repair and facilitates viral genome replication.","authors":"Igor Etingov, David J Pintel","doi":"10.1128/jvi.00889-24","DOIUrl":"10.1128/jvi.00889-24","url":null,"abstract":"<p><p>During infection, the autonomous parvovirus minute virus of mice (MVM) induces cellular DNA breaks and localizes to such sites, which presumably affords an environment beneficial for genome replication. MVM replication also benefits from the DNA damage response (DDR) mediated by the ataxia-telangiectasia mutated (ATM) kinase, while the ataxia telangiectasia and Rad-3 related (ATR) arm of the DDR is disabled, which prevents activation of its primary target, checkpoint kinase 1 (Chk1). We find here that Chk1 inactivation strongly correlates with dephosphorylation of one of its targets, RAD51, known to play a pivotal role in homologous recombination repair (HRR), thus leading to substantial inhibition of DNA repair in infected cells. We demonstrate colocalization of replicating MVM DNA with cellular double-strand breaks (DSBs) during infection, and show that an agent that exogenously induces cellular DSBs significantly increases viral DNA replication levels, establishing a role for cellular genome damage in facilitating virus DNA replication. Additionally, overexpression of active Chk1 during MVM infection was found to re-establish the activating phosphorylation of RAD51 Thr 309, significantly suppress infection-induced reduction of HRR efficiency with a concomitant increase in cellular genome DSBs, and reduce viral DNA replication levels. Thus, we conclude that during infection, MVM inhibition of Chk1 activation enhances viral replication, at least in part, by inhibiting cellular HRR.IMPORTANCEThe autonomous parvovirus minute virus of mice (MVM) has a compact DNA genome encoding a minimum number of proteins. During infection, it induces cellular DNA damage and both utilizes and modifies the subsequent cellular DNA damage response (DDR) in various ways to facilitate its replication. One of MVM's activities in this regard is to inhibit one of the primary arms of the DDR, the ataxia telangiectasia and Rad-3 related (ATR) pathway, which prevents activation of checkpoint kinase 1 (Chk1), a key protein involved in controlling the cellular DDR and preserving genome integrity. We show that prevention by MVM of Chk1 activation leads to inhibition of homologous recombination repair (HRR) of cellular DNA, which helps sustain viral replication. This work illuminates another way in which autonomous parvoviruses adjust the cellular environment for their replicative advantage.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0088924"},"PeriodicalIF":4.0,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11650968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD6 regulates CD4 T follicular helper cell differentiation and humoral immunity during murine coronavirus infection.","authors":"Amber Cardani-Boulton, Feng Lin, Cornelia C Bergmann","doi":"10.1128/jvi.01864-24","DOIUrl":"10.1128/jvi.01864-24","url":null,"abstract":"<p><p>During activation, the T cell transmembrane receptor CD6 becomes incorporated into the T cell immunological synapse where it can exert both co-stimulatory and co-inhibitory functions. Given the ability of CD6 to carry out opposing functions, this study sought to determine how CD6 regulates early T cell activation in response to viral infection. Infection of CD6-deficient mice with a neurotropic murine coronavirus resulted in greater activation and expansion of CD4 T cells in the draining lymph nodes. Further analysis demonstrated that there was also preferential differentiation of CD4 T cells into T follicular helper cells, resulting in accelerated germinal center responses and emergence of high-affinity virus-specific antibodies. Given that CD6 conversely supports CD4 T cell activation in many autoimmune models, we probed potential mechanisms of CD6-mediated suppression of CD4 T cell activation during viral infection. Analysis of CD6 binding proteins revealed that infection-induced upregulation of <i>Ubash3a</i>, a negative regulator of T cell receptor (TCR) signaling, was hindered in CD6-deficient lymph nodes. Consistent with greater T cell activation and reduced UBASH3a activity, the T cell receptor signal strength was intensified in CD6-deficient CD4 T cells. These results reveal a novel immunoregulatory role for CD6 in limiting CD4 T cell activation and deterring CD4 T follicular helper cell differentiation, thereby attenuating antiviral humoral immunity.</p><p><strong>Importance: </strong>CD6 monoclonal blocking antibodies are being therapeutically administered to inhibit T cell activation in autoimmune disorders. However, the multifaceted nature of CD6 allows for multiple and even opposing functions under different circumstances of T cell activation. We therefore sought to characterize how CD6 regulates T cell activation in the context of viral infections using an <i>in vivo</i> murine coronavirus model. In contrast to its role in autoimmunity, but consistent with its function in the presence of superantigens, we found that CD6 deficiency enhances CD4 T cell activation and CD4 T cell help to germinal center-dependent antiviral humoral responses. Finally, we provide evidence that CD6 regulates transcription of its intracellular binding partner UBASH3a, which suppresses T cell receptor (TCR) signaling and consequently T cell activation. These findings highlight the context-dependent flexibility of CD6 in regulating <i>in vivo</i> adaptive immune responses, which may be targeted to enhance antiviral immunity.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0186424"},"PeriodicalIF":4.0,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142829175","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}