Journal of Virology最新文献

{"title":"Avian leukosis virus p15 interacts with interferon regulatory factor 7 to antagonize the cGAS-STING signaling pathway and promote viral replication.","authors":"Zhouhao Cui, Kui Shen, Moru Xu, Yongxiu Yao, Hongxia Shao, Aijian Qin, Kun Qian","doi":"10.1128/jvi.00380-25","DOIUrl":"10.1128/jvi.00380-25","url":null,"abstract":"<p><p>Cyclic GMP-AMP synthase (cGAS) recognizes viral DNA within the cytoplasm and initiates innate antiviral response through the cGAS-STING pathway. However, viruses have evolved diverse strategies to counteract the cGAS-STING signaling pathway. Avian leukosis virus subgroup J (ALV-J), an avian oncogenic retrovirus, can antagonize host innate immune responses and cause immunosuppression to develop tumors. In this study, with a functional screen, we identified the p15 protein, a protease encoded by ALV-J, inhibiting the cGAS-STING signaling pathway and IFN-β production to promote virus replication. This inhibitory effect is associated with the enzymatic active site of p15. Further study demonstrated that the p15 protein interacted with the DBD domain of interferon regulatory factor 7 (IRF7), inhibiting the dimerization and nuclear translocation of IRF7 but not the phosphorylation of IRF7, resulting in the suppression of IFN-β production. Consistent with these results, small-interfering RNA targeting p15 in ALV-J infection induced more IFN-β in DF-1 cells compared with control RNA. Taken together, these results verified that ALV-J-encoded p15 protein plays a key role in evading the cGAS-STING pathway, which improves our understanding of the virus-host interaction in ALV-J evading host innate immunity and may contribute to developing novel drugs against ALV-J infection.</p><p><strong>Importance: </strong>Among all subgroups, avian leukosis virus subgroup J is one of the most pathogenic, capable of inducing severe malignant tumors and immunosuppressive effects on the infected host. Although there have been some reports on the immunosuppressive mechanisms of ALV-J, the immune evasion mechanism mediated by ALV-J-encoded proteins remains largely unknown. In this study, we found that p15 interacted with IRF7 and inhibited the dimerization and nuclear translocation of IRF7, resulting in the suppression of the expression of IFN-β. Of note, the results demonstrated that the enzymatic active site of p15 (37D, 38S) plays a crucial role in this process. Our findings revealed that p15 enhanced ALV-J replication by inhibiting the cGAS-STING signaling pathway, which highlights the possibility of p15 as a potential drug target.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0038025"},"PeriodicalIF":3.8,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12363237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144698914","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 vaccinia virus protein, C16, promotes the ubiquitylation and relocalization of the antiviral E3 ubiquitin-ligase, TRIM25.","authors":"Jianing Dong, Shu Yue Luo, Summer Smyth, Grace Melvie, Olivier Julien, Robert J Ingham","doi":"10.1128/jvi.00898-25","DOIUrl":"10.1128/jvi.00898-25","url":null,"abstract":"<p><p>Poxviruses co-opt the ubiquitin (Ub)-proteasome system (UPS) to facilitate virus replication, evade the innate immune response, and block programmed cell death of infected cells. Moreover, the UPS is an integral component of innate immune signaling pathways used by the host to respond to infection. To further elucidate how the UPS is engaged early during poxvirus infection, we quantified viral and cellular peptides with a Ub remnant motif (diGly peptides) from lysates of uninfected and vaccinia virus Copenhagen strain (VACV-Cop)-infected HeLa cells. Of note, we identified several ubiquitylated peptides from the cellular antiviral protein, TRIM25, that were enriched for, or exclusively found, in VACV-Cop-infected cells. TRIM25 is an E3 ligase for Ub and the Ub-like protein, ISG15, and TRIM25 performs several functions including activating the type I interferon response. Higher-molecular weight, ubiquitylated TRIM25 species were evident as early as 1 h post-infection of HeLa cells with VACV-Cop, and they persisted throughout infection. Proteasomal or lysosomal degradation did not appear to be a major consequence of this ubiquitylation; however, TRIM25 ubiquitylation correlated with its relocalization to punctate structures in infected cells. C16, a Bcl-2 family-like protein encoded by identical genes on both arms of the VACV-Cop genome, was both necessary and sufficient to promote TRIM25 ubiquitylation and relocalization. These phenomena were not evident in cells infected with Orthopoxviruses lacking the genes encoding for C16. We postulate that the ubiquitylation and/or relocalization of TRIM25 induced by C16 could represent a novel mechanism for poxviruses to subvert the host antiviral response.IMPORTANCEUbiquitylation is a versatile post-translational modification that is required for poxviruses to replicate their genomes and evade host cell defenses to infection. At the same time, both degradative and non-degradative protein ubiquitylation are critical components of the innate and adaptive immune responses to infection. In this study, we opted for a proteomics approach to examine changes in protein ubiquitylation early after vaccinia virus infection with the goal of identifying novel ways by which ubiquitylation is exploited during infection. We demonstrate that many Orthopoxviruses utilize the Bcl-2 family-like protein C16 to promote the ubiquitylation and relocalization of the cellular E3 ubiquitin/ISG15-ligase, TRIM25, which we hypothesize represents a novel strategy by which these viruses evade the host cell antiviral response. Moreover, our findings hint that Orthopoxviruses may also have C16-independent strategies to interfere with the function of TRIM25.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0089825"},"PeriodicalIF":3.8,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12363216/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732009","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":"Transferrin receptor 1 (TfR1) functions as an entry receptor for scale drop disease virus to invade the host cell via clathrin-mediated endocytosis.","authors":"Jiaming Chen, Yuting Fu, Yong Li, Shaoping Weng, Hebing Wang, Jianguo He, Chuanfu Dong","doi":"10.1128/jvi.00671-25","DOIUrl":"10.1128/jvi.00671-25","url":null,"abstract":"<p><p>Scale drop disease virus (SDDV), a distinct member of the genus <i>Megalocytivirus</i> within the <i>Iridoviridae</i> family, has emerged as a novel threat to global teleost aquaculture. Despite its importance, the pathogenic mechanism of SDDV remains largely elusive. In this study, we identified mandarin fish transferrin receptor 1 (<i>mf</i>TfR1) as an entry receptor for SDDV to invade host cells. First, <i>mf</i>TfR1 was detected in high abundance in purified SDDV virions and exhibited dynamic responses to SDDV infection, showing distinct regulatory patterns both <i>in vivo</i> and <i>in vitro</i>. Overexpression of <i>mf</i>TfR1 in low-permissive fathead minnow (FHM) cells significantly enhanced SDDV replication, particularly during the early stages of viral binding and entry. Conversely, antibody-blocking experiments and treatment with the TfR1 inhibitor ferristatin II significantly suppressed SDDV entry. Further investigation revealed that <i>mf</i>TfR1 directly interacted with the major capsid protein (MCP) of SDDV, and the helical domain of <i>mf</i>TfR1 was identified as the crucial docking site. The binding site within the helical domain was determined, and disrupting this interaction significantly reduced viral entry and host mortality. Finally, we demonstrated that SDDV could activate Src kinase-mediated tyrosine phosphorylation of <i>mf</i>TfR1. This phosphorylation event enhanced the internalization of <i>mf</i>TfR1 and facilitated clathrin-mediated endocytosis. Collectively, our study provides compelling evidence to confirm that <i>mf</i>TfR1 functions as an entry receptor that mediates SDDV entry into host cells via clathrin-mediated endocytosis, leading to a lethal infection outcome. Our work lays the groundwork for the development of targeted therapeutic strategies to mitigate the impact of SDDV in aquaculture.IMPORTANCETfR1, a dimeric glycoprotein classified as a type II transmembrane receptor, facilitates the cellular internalization of holo-transferrin. In several mammalian and avian RNA viruses and small DNA viruses, TfR1 serves as a crucial receptor to mediate the entry of viruses into host cells. As an emerging large DNA virus, SDDV poses an emerging threat to teleosts globally; however, its underlying pathogenic mechanisms remain poorly understood. In this study, we are the first to identify <i>mf</i>TfR1 as a crucial receptor for SDDV entry. We demonstrated a specific interaction between <i>mf</i>TfR1 and the major capsid protein (MCP) of SDDV, with the helical domain of <i>mf</i>TfR1 acting as the binding site. Moreover, we confirmed that SDDV enters cells through <i>mf</i>TfR1-mediated clathrin-dependent endocytosis. This work highlights the essential role of TfR1 in aquatic DNA viral infections and establishes the theoretical foundation for developing targeted therapeutic strategies against SDDV.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0067125"},"PeriodicalIF":3.8,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12363161/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732010","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":"Genome integration of human DNA oncoviruses.","authors":"Zuzana Vojtechova, Ruth Tachezy","doi":"10.1128/jvi.00562-25","DOIUrl":"10.1128/jvi.00562-25","url":null,"abstract":"<p><p>Tumors of infectious origin globally represent 13%. Oncogenic DNA viruses such as human papillomavirus (HPV), hepatitis B virus (HBV), and Epstein-Barr virus (EBV) are responsible for approximately 60% of these tumors. These oncoviruses are extensively studied to understand their role in cancer development, particularly through viral genome integration into the host DNA. Retroviruses require integration mediated by viral integrase for persistence, whereas DNA oncoviruses do not need integration for replication; instead, integration occurs incidentally. This process often targets fragile sites in the human genome, causing structural rearrangements that disrupt genes, activate proto-oncogenes, and increase genomic instability, all contributing to tumorigenesis. Integration near promoter regions and active genes is closely linked to carcinogenesis, highlighting its importance in developing diagnostic and therapeutic strategies. This review summarizes viral integration's role in oncogenesis, mechanisms of integration, and methods to study this process, focusing on DNA tumor viruses such as HBV, EBV, HPV, and Merkel cell polyomavirus.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0056225"},"PeriodicalIF":3.8,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12363244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144690660","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":"Novel insights into immune checkpoints in HIV/SHIV infection: from SHIV_SF162P3-infected elite controllers to therapeutic strategy.","authors":"Yuting Sun, Chenbo Yang, Peiwen Liu, Zhe Cong, Jiahui Luo, Ling Tong, Jingjing Zhang, Jiahan Lu, Ziqing Jia, Lin Zhu, Qiuhan Lu, Ting Chen, Qiang Wei, Dan Li, Rui Hou, Jing Xue","doi":"10.1128/jvi.00785-25","DOIUrl":"10.1128/jvi.00785-25","url":null,"abstract":"<p><p>During chronic HIV-1 infection, the upregulation of immune checkpoints (ICs) on lymphocytes contributes to persistent immune dysfunction, T-cell exhaustion, and inadequate virological control, highlighting the potential role of ICs in HIV functional cure strategy. Despite extensive research on ICs, the expression dynamics and immunological impact of ICs in natural HIV/SHIV infection, particularly among antiretroviral therapy (ART)-free elite controllers (ECs), remain poorly understood. In this study, we monitored a cohort of SHIV_SF162P3-infected rhesus macaques (RMs), identifying four ECs and four progressors (PGs) through longitudinal evaluation. We observed low-level expression of ICs in both peripheral blood and lymph nodes of ECs, characterized by a particularly pronounced restriction in the expression of TIGIT and BTLA. This attenuated IC profile correlated with enhanced T-cell functionality, reduced exhaustion markers, and reduced viral reservoirs in peripheral and lymphoid tissues. Transcriptomic profiling revealed that TIGIT is a critical checkpoint marker involved in multiple synergistic cofunctions related to HIV/SIV-specific immune regulation. Collectively, our findings establish a dual role for ICs in perpetuating T-cell exhaustion and viral reservoir persistence, paving the way for IC blockade in future HIV cure strategies.IMPORTANCERhesus macaques spontaneously controlling simian-human immunodeficiency virus (SHIV) without antiretroviral therapy have low-level expression of immune molecules (ICs), characterized by TIGIT and BTLA. These molecules are linked to enhanced immune function and reduced viral presence in peripheral blood and lymph nodes. Transcriptomic profiling revealed that TIGIT is a critical checkpoint marker involved in multiple synergistic cofunctions related to HIV/SIV-specific immune regulation in both humans and macaques. Blocking TIGIT improved polyfunctional T-cell responses, thereby offering a potential new treatment strategy and providing critical insights for developing a functional HIV cure.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0078525"},"PeriodicalIF":3.8,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12363197/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144600872","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":"Mutations differentially affecting the coronavirus Mac1 ADP-ribose binding and hydrolysis activities indicate that it promotes multiple stages of the viral replication cycle.","authors":"Joseph J O'Connor, Anuradha Roy, Reem Khattabi, Catherine Kerr, Nancy Schwarting, Yousef M Alhammad, Philip Gao, Xiaoming Zhang, Xufang Deng, Anthony R Fehr","doi":"10.1128/jvi.00623-25","DOIUrl":"10.1128/jvi.00623-25","url":null,"abstract":"<p><p>All coronaviruses (CoVs) encode a conserved macrodomain, termed Mac1, in non-structural protein 3 (nsp3) that binds and hydrolyzes ADP-ribose covalently attached to proteins. Mac1 is a key virulence factor that counters antiviral ADP-ribosyltransferase (PARP) activity. Previously, we found that MHV strain JHM (JHMV) with a mutation in the adenine binding site, JHMV-D1329A, was extremely attenuated in all tested cell types as opposed to JHMV-N1347A, which only has a replication defect in bone marrow-derived macrophages (BMDMs). Interestingly, an N1347A/D1329A double mutant was unrecoverable, indicating an essential role for Mac1 in JHMV infection. We hypothesized that these mutations may impact different stages of the MHV life cycle. First, to clarify how these mutations affected the biochemical activities of Mac1, we generated Mac1 proteins encoding the same mutations. As expected, the D-A mutation was extremely defective in ADP-ribose binding but maintained enzyme activity. In contrast, we previously found that the N-A mutation had WT levels of ADP-ribose binding but low enzyme activity, confirming that these mutations differentially affect the biochemical functions of Mac1. Following infection, D1329A displayed a large defect in the accumulation of viral RNA compared to WT or N1347A in all cells tested. Alternatively, N1347A infection produced normal levels of viral RNA but produced reduced levels of viral protein in interferon-competent bone marrow-derived macrophages (BMDMs). These results suggest that Mac1 ADP-ribose binding and enzymatic activities promote different stages of the viral life cycle, demonstrating the critical importance of Mac1 for JHMV replication.</p><p><strong>Importance: </strong>Over the last three decades, coronaviruses have repeatedly demonstrated their potential to become significant veterinary and public health threats. Zoonotic transmission of the myriad known coronavirus strains will remain a concern, regardless of the advances in vaccines and treatment. One difficulty in anticipating the next coronavirus outbreak is its diverse lineage and high propensity for mutation and recombination. The coronavirus macrodomain, Mac1, is conserved among all known coronaviruses and is also conserved in the <i>Togaviridae</i> and <i>Hepeviridae</i> families. Mac1 is a key factor in viral replication and pathogenesis, but its role in the replication cycle remains unclear. A deeper investigation of Mac1 function will identify conserved antiviral mechanisms and aid in the development of Mac1 inhibitors that represent a novel strategy for antiviral therapeutics.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0062325"},"PeriodicalIF":3.8,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12363162/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144742353","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":"A novel replication-deficient FCV vaccine provides strong immune protection in cats.","authors":"Wuchang Heng, Dan Zang, Ruiyu Li, Qian Jiang, Jiasen Liu, Honglin Jia, Hongtao Kang","doi":"10.1128/jvi.00093-25","DOIUrl":"10.1128/jvi.00093-25","url":null,"abstract":"<p><p>Feline calicivirus (FCV) belongs to the family Caliciviridae, which includes important animal and human pathogens such as human norovirus and rabbit hemorrhagic disease virus. The fast evolution and great diversity of FCV make it highly difficult to develop vaccines that can induce sterilizing immunity. In this study, we evaluated the efficacy of a vaccine candidate generated via a replication-deficient vaccine strategy. Immunization with the vaccine generated a high level of neutralizing antibodies and highly reduced clinical outcomes against the challenge with a homologous virulent systemic feline calicivirus (VS-FCV) strain. Moreover, the VP1 gene of the vaccine was replaced with that derived from a heterologous virus strain. Vaccination with two combined virus constructs containing genetically distant VP1 genes led to the generation of broad neutralizing antibodies against FCV strains in cats. Notably, this replication-deficient FCV has the potential to serve as a viral vector vaccine, enabling the delivery of a foreign gene with stable genetics. In summary, this vaccine strategy holds great promise for developing safe, effective, and multivalent vaccines to prevent and control calicivirus infection.IMPORTANCEFCV is one of the leading causes of respiratory diseases in cats. Over the last 20 years, certain strains evolved into VS-FCV, with severe symptoms and increased fatality. Updating and developing vaccines promptly are essential. Here, we employed reverse genetics to partially delete the VP2 gene of FCV, rescuing the replication-deficient vaccine candidate rHBDL2 FCV-△VP2. Immunization with this candidate generated high levels of neutralizing antibodies against FCV strains and significantly reduced clinical symptoms. Furthermore, the adaptability of this replication-defective FCV platform holds potential for the development of viral vector vaccines as well as multivalent vaccines, which are also crucial for the prevention and control of other calicivirus infections.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0009325"},"PeriodicalIF":3.8,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12363202/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144584250","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":"Mucosal vaccination with long-form TSLP induces migratory cDC1-mediated adaptive immunity against SARS-CoV-2 infection.","authors":"Jing Hu, Housheng Zheng, Wei Ran, Xuefei Wang, Chenghui Liao, Jian Zhou, Liang Ye","doi":"10.1128/jvi.01231-25","DOIUrl":"10.1128/jvi.01231-25","url":null,"abstract":"<p><p>A combination of vaccination strategies will potentially be required for effective control of the virus pandemic. We report that mice intranasally immunized with commercial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) subunit vaccines enriched with the human thymic stromal lymphopoietin (TSLP) variant, long-form TSLP (lfTSLP), but not the short-isoform TSLP (sfTSLP), induced robust antigen-specific systemic and mucosal antibody production. The adjuvant-enhancing activity of lfTSLP in mice requires functional TSLP receptor signals in migratory type 1 conventional dendritic cells (cDC1s). Furthermore, lfTSLP acts on migratory cDC1s to enhance T follicular helper (Tfh) cell and germinal center (GC) B cell responses. Intranasal vaccination with lfTSLP elicits long-lasting immunogenicity and protection against the challenge of wild-type SARS-CoV-2 and the B.1.617.2 variant in mice. Our study provides insights into the adjuvant role of lfTSLP, which is critical in enhancing migratory cDC1-mediated GC responses to improve vaccine efficacy.</p><p><strong>Importance: </strong>Adjuvants are indispensable components of subunit vaccines, and the development of adjuvants capable of inducing powerful systemic and mucosal immune responses is critical for enhancing the efficacy of viral vaccines. This study reveals that the human long-form thymic stromal lymphopoietin (lfTSLP) induces antigen-specific systemic IgG and mucosal IgA antibody production with sustained immunogenicity. Mechanistically, lfTSLP enhances germinal center reactions by preferentially activating migratory type 1 conventional dendritic cells (cDC1s). These findings uncover a previously unrecognized mechanism underlying the adjuvant activity of lfTSLP, which enhances vaccine-induced adaptive immunity and confers protection against SARS-CoV-2 infection. These findings indicate that the application of lfTSLP as an adjuvant should be encouraged in the rational design and development of viral vaccines.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0123125"},"PeriodicalIF":3.8,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144873853","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 HCMV tegument protein UL88 degrades MyD88 and reduces innate immune activation.","authors":"Rinki Kumar, Irene E Reider, Madison Martin, Julia S Simpson, Nicholas J Buchkovich, Christopher C Norbury","doi":"10.1128/jvi.00414-25","DOIUrl":"10.1128/jvi.00414-25","url":null,"abstract":"<p><p>The human cytomegalovirus (HCMV) encodes the tegument protein UL88, which supports virus spread by mediating the degradation of the innate immune signaling adapter protein, myeloid differentiation primary response 88 (MyD88). MyD88 transduces signals in multiple innate immune pathways, including acting downstream of pattern recognition receptors and IL-1 cytokine family members. MyD88 is rapidly and robustly upregulated following exposure to HCMV, irrespective of viral gene expression and, even after infection, primarily within uninfected cells in a culture. However, UL88 was required to downregulate cellular MyD88 protein levels as HCMV spread through a culture. The N-terminal 181 amino acids of UL88 were required to associate with and downregulate MyD88 protein. MyD88 expression significantly suppressed virus spread by triggering the production of a heat-labile soluble factor. This factor was produced between ~3 and 6 days after initial infection and did not increase the expression of well-characterized interferon-stimulated genes (ISGs). Indeed, increased MyD88 expression downregulated the expression of almost all ISGs examined. UL88 overexpression suppressed IL-1β-induced NF-κB activation within a cell. UL88 also suppressed virus-induced translocation of NF-κB to the nucleus of uninfected neighboring cells in an infected monolayer. Furthermore, UL88 overexpression was required for effective HCMV spread following transfer of the virus from monocytes to a fibroblast monolayer. These data indicate that UL88 is a novel antagonist of the immune response that acts to enhance the natural spread of HCMV by targeting MyD88 and provides vital insight into the innate immune responses that can control HCMV spread.IMPORTANCEThe significant role of many viral genes encoded by HCMV that are not essential for replication in cell culture is often overlooked. Our study reveals the importance of UL88 for regulating the innate immune response by showing evidence for interaction with and downregulation of MyD88 protein. The UL88-dependent regulation of MyD88 is physiologically relevant, as infection is enhanced in the absence of MyD88, and spread from myeloid cells to fibroblasts is blunted in the absence of UL88. These results highlight yet another important interaction between HCMV and the immune system.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0041425"},"PeriodicalIF":3.8,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12363176/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144600873","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":"CX1/BtSY2 and BANAL-20-52 exhibit broader receptor binding and higher affinities to multiple animal ACE2 orthologs than SARS-CoV-2 prototype.","authors":"Zepeng Xu, Linjie Li, Yuhang Gu, Dedong Li, Jianxun Qi, Kefang Liu, Chu-Xia Deng, George Fu Gao","doi":"10.1128/jvi.00283-25","DOIUrl":"10.1128/jvi.00283-25","url":null,"abstract":"<p><p>Animal coronaviruses (CoVs) CX1 (formerly named BtSY2) and BANAL-20-52 are phylogenetically closely related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and CX1 is the first observed animal betaCoV carrying naturally occurring Y501 in its receptor-binding domain (RBD) of the spike (S) protein, a residue related to human adaptation and broader host range. We evaluated the ACE2 usage of CX1 and BANAL-20-52 and observed broader receptor binding spectra and higher affinities to most of the tested animal ACE2 orthologs than the SARS-CoV-2 prototype. Determination of the cryo-EM structures of their S proteins and RBD/hACE2 complexes reveals that Y501 is inter-replaceable with H498 substitution while synergetic with R498 for human ACE2 binding. These results provide further structural insights into SARS-CoV-2 receptor recognition and address the importance of surveillance on potential emerging CoVs.IMPORTANCESince the outbreak of COVID-19, forewarning and prevention of the next pandemic have been widely discussed. Coronaviruses (CoVs) CX1 (formerly named BtSY2) and BANAL-20-52 are phylogenetically closely related to SARS-CoV-2. Particularly, CX1 is the first SARS-CoV-2-related CoV containing Y501 in its receptor-binding domain (RBD) of the spike (S) protein. This study evaluated the interspecies transmission potential of the two CoVs and structurally elucidated the interplay between two RBD residues 498 and 501 on ACE2 binding, further highlighting the importance of surveillance on zoonotic CoVs.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0028325"},"PeriodicalIF":3.8,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12363175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144600871","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}