Journal of Virology最新文献

{"title":"GCN2 enhances host survival and drives eIF2α phosphorylation during mouse adenovirus type 1 infection.","authors":"Luiza A Castro Jorge, Daniel F Edwards, Rosario Labastida, Danielle E Goodman, Estela A Pereira, Oded Foreman, Katherine R Spindler","doi":"10.1128/jvi.01288-25","DOIUrl":"https://doi.org/10.1128/jvi.01288-25","url":null,"abstract":"<p><p>The integrated stress response (ISR) is a cellular signaling pathway that reduces protein synthesis in the face of cellular stress, including viral infection. Two eukaryotic initiation factor 2α (eIF2α) kinases, protein kinase R (PKR) and general control nonderepressible 2 (GCN2), are commonly activated during viral infections. Mouse adenovirus type 1 (MAV-1) infection leads to a steep reduction of PKR levels by proteasomal degradation. We assayed whether GCN2, a sensor of amino acid starvation and UV damage, plays a role in the ISR to MAV-1 infection. There was more phosphorylated GCN2 in MAV-1-infected cells, and its activation was dependent on virus replication since UV-inactivated virus was not able to increase the phosphorylation of GCN2. Infected <i>Eif2ak4^tm1.2Dron</i> mice (designated here <i>Gcn2^-/</i>^- mice) had lower survival than wild-type (WT) mice, but results indicated that this was not due to increased viral replication. Both <i>Gcn2^-/</i>^- and WT mice developed multifocal brain parenchymal microhemorrhages during infection. While <i>Gcn2^-/</i>^- animals had more lesions, their higher mortality is likely not due to the microhemorrhages alone. Cytokine RNA and protein assays of WT and <i>Gcn2^-/</i>^- mice only showed a difference for IL- β levels, which were higher in <i>Gcn2^-/</i>^- mice. Our results also indicate that of the two eIF2α kinases, PKR and GCN2, GCN2 is the primary inducer of phosphorylated-eIF2α during MAV-1 infection. GCN2 is thus antiviral and contributes to the host response to MAV-1 infection.IMPORTANCECells often respond to viral infection by activation of the host protein kinase R (PKR), part of the integrated stress response (ISR). We show that a second host protein kinase, general control nonderepressible 2 (GCN2), is activated by phosphorylation in response to mouse adenovirus type 1 (MAV-1) infection. Our results indicate GCN2 is antiviral: without it, the mortality in MAV-1-infected mouse is higher. Furthermore, the data show that GCN2, rather than PKR, is the main inducer of eIf2α phosphorylation (and thus the ISR) upon MAV-1 infection. This is consistent with PKR exerting antiviral effects in MAV-1 infections through a pathway independent of eIf2α phosphorylation.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0128825"},"PeriodicalIF":3.8,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145131224","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":"Cytoplasmic translocation of tripartite motif-containing 28 is critical for PRRSV-induced autophagy through promoting Vps34-Beclin1 complex formation.","authors":"Meng Chen, Yuna Zhao, Hui An, Qingbing Han, Chenchen Cui, Jun Peng, Yihong Xiao, Gang Wang, Yingli Shang","doi":"10.1128/jvi.01133-25","DOIUrl":"10.1128/jvi.01133-25","url":null,"abstract":"<p><p>Autophagy, as a highly conserved cellular metabolic regulation mechanism, is a double-edged sword and plays multiple roles in viral infections processes. As a member of the Arteriviridae family within the order Nidovirales, the porcine reproductive and respiratory syndrome virus (PRRSV) induces cell autophagy both <i>in vitro</i> and <i>in vivo</i>. However, the direct or indirect causation of autophagy by PRRSV remains unclear. Identified as an autophagy-related factor, tripartite motif-containing 28 (TRIM28) shows an undefined relationship with autophagy during PRRSV infection. This study investigates the dynamic changes in autophagy and TRIM28 during PRRSV infection, revealing that PRRSV Nsp4 is identified as a key component responsible for the nuclear export of TRIM28 via a CRM1-dependent pathway, promoting the formation of the Vps34-Beclin1 complex and ultimately initiating autophagy. As a host protein, TRIM28 has exerted a certain antiviral effect, but the mechanism is not yet clear. This study provides detailed insight into the mechanism of PRRSV-mediated autophagy for the first time, offering valuable information for understanding the pathogenesis of porcine reproductive and respiratory syndrome.</p><p><strong>Importance: </strong>PRRS is one of the major diseases affecting the global swine industry. Infection with PRRSV can cause respiratory disease in pigs of all ages and reproductive disorders in sows. Therefore, understanding the interaction between PRRSV and host factors may help to develop new antiviral strategies against PRRSV. We found that PRRSV Nsp4 was important for nuclear export of TRIM28 in a CRM1-dependent manner during PRRSV infection. TRIM28 in the cytoplasm increases the formation of VPS34-Beclin1 complex by interacting with Vps34, further initiating autophagy. Hence, our study reveals a novel mechanism of PRRSV-mediated autophagy and provides valuable information for further understanding the pathogenesis of PRRS, which might contribute to the development of novel antiviral drugs.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0113325"},"PeriodicalIF":3.8,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145131192","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":"ASFV pE146L-induced ER remodeling is essential for viral replication.","authors":"Yilin Guo, Sai Niu, Xueying Wang, Zixuan Wang, Rui Liang, Yubei Tan, Zhen Fu, Zhelin Su, Juan Xu, Hongjun Chen, Yuejun Shi, Limeng Sun, Guiqing Peng","doi":"10.1128/jvi.00834-25","DOIUrl":"10.1128/jvi.00834-25","url":null,"abstract":"<p><p>African swine fever virus (ASFV) causes a severe hemorrhagic disease, posing a significant threat to the global pig industry. Although the ASFV encodes nearly 200 proteins, the functions of many remain unknown. Here, we identify the inner envelope protein pE146L as essential for ASFV replication. pE146L, localized in the endoplasmic reticulum lumen, induces endoplasmic reticulum (ER) perinuclear aggregation, and its absence disrupts viral factory formation. Mechanistic studies revealed the first high-resolution crystal structure of pE146L-ΔTM. Structural and biochemical analyses revealed that disrupting the intermolecular disulfide bonds of the dimers (C103A) abrogates ER aggregation and impedes viral replication. Furthermore, pE146L binds lipids via a positively charged surface patch, a function critical for replication, suggesting a role in lipid regulation. These findings highlight the multifunctionality of pE146L in ASFV morphogenesis and provide a promising target for anti-ASFV drug development.</p><p><strong>Importance: </strong>African swine fever virus (ASFV) causes a highly lethal infectious disease in swine; however, our understanding of its replication and assembly mechanisms remains limited, which hinders the development of vaccines and drugs. In this study, we identified the uncharacterized pE146L, a protein of the inner envelope that is required for the viral life cycle. Notably, we found that pE146L showed distinct colocalization and the ability to induce noticeable ER aggregation. Moreover, we solved the first high-resolution crystal structure of the extracellular soluble region of pE146L and discovered that it is a lipid-binding protein. Interestingly, structural and biochemical analyses suggest the potentially significant impact of intermolecular disulfide bonds on ER aggregation and viral replication. These results highlight the multifunctionality of ASFV pE146L, providing new insights for the development of specific antiviral drugs.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0083425"},"PeriodicalIF":3.8,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12455986/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144789495","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":"Structural dissection of vaccinia G9 identifies residues essential for membrane fusion and complex assembly.","authors":"Hsiao-Jung Chiu, Hao-Ching Wang, Wen Chang","doi":"10.1128/jvi.00723-25","DOIUrl":"10.1128/jvi.00723-25","url":null,"abstract":"<p><p>Vaccinia virus, a prototypical poxvirus, utilizes a unique multi-protein entry fusion complex (EFC), comprising 11 components, to mediate membrane fusion during host cell entry. Although the crystal structure of a truncated form of the G9 protein has been determined, the functional relevance of its structural features remains poorly understood. In this study, we systematically analyzed 47 G9 mutants to identify critical functional residues. Using trans-complementation assays, co-immunoprecipitation, membrane fusion assays, and structural analysis, we identified nine key mutants, which were categorized into three functional groups. Group 1 mutants failed to interact with A16 and other EFC components, highlighting their essential roles in G9-A16 subcomplex formation. Group 2 and Group 3 mutants retained A16 binding but disrupted interactions with other EFC proteins, suggesting their roles in broader complex assembly. Notably, Group 3 mutants targeted a conserved P(R/Y)XCW motif and a loop structure shared among vaccinia G9, A16, and J5 proteins. A similar motif was also identified in G9 homologs from <i>Nucleocytoviricota</i>, suggesting an evolutionarily conserved fusion mechanism. Collectively, our findings demonstrated that G9 function requires multiple domains, including A16-binding interfaces and conserved motifs not resolved in previous protein structures. These results establish G9 as a central EFC component and underscore its potential as a target for antiviral development.IMPORTANCEUnderstanding how viruses enter host cells is critical for developing antiviral strategies. Vaccinia virus, a model poxvirus, uses a unique 11-protein entry fusion complex (EFC) to mediate membrane fusion, unlike other viruses that rely on a single fusion protein. In this study, we identified specific residues in the G9 protein that are critical for maintaining EFC function. Notably, we discovered a conserved P(R/Y)XCW motif within G9 that is also present in orthologs from both poxviruses and members of the <i>Nucleocytoviricota</i> phylum, suggesting an evolutionarily conserved mechanism of membrane fusion. These conserved structural elements can serve as potential targets for antiviral intervention against pathogenic poxvirus infections in humans.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0072325"},"PeriodicalIF":3.8,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12456145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144873854","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":"Coatomer protein complex I is required for efficient secretion of dengue virus non-structural protein 1.","authors":"Stephen M Johnson, Siena M Centofanti, Gustavo Bracho, Michael R Beard, Jillian M Carr, Nicholas S Eyre","doi":"10.1128/jvi.00962-25","DOIUrl":"10.1128/jvi.00962-25","url":null,"abstract":"<p><p>Secreted non-structural protein 1 (sNS1) is an important orthoflavivirus pathogenic factor that can induce vascular leakage, a key symptom of severe dengue disease. Given the role of sNS1 in dengue pathogenesis, defining the molecular mechanisms of NS1 secretion may contribute to the development of NS1-targeting antiviral therapies. To this end, we performed a customized membrane-trafficking siRNA screen to identify human host factors involved in NS1 secretion. Our screen identified COPA, COPB2, and COPG1 as the top-ranking hits. These proteins are three of the seven subunits of the coatomer protein complex I (COPI) that coat transport vesicles that operate within the early secretory pathway, implicating COPI machinery as being involved in NS1 secretion. Validation studies employing host gene knockdown in dengue virus (DENV)-infected cells confirmed that COPI components are required for efficient NS1 secretion but are dispensable for infectious virus egress. Similar reductions in NS1 secretion were observed when COPI components were depleted in cells infected with West Nile virus Kunjin subtype (WNV/KUNV), indicating that the molecular mechanisms exploited to achieve NS1 secretion may be a conserved feature within the Orthoflavivirus genus. Heterologous expression of wild-type and pathogenic COPI variants in DENV NS1-NS5 polyprotein-expressing cells resulted in altered NS1 secretion profiles, suggesting that allelic variants and altered expression levels of COPI components may indirectly influence the severity of dengue disease. The identification of COPI components as important determinants of NS1 secretion efficiency may aid in the identification of novel targets for anti-orthoflaviviral therapies.IMPORTANCEOver half of the world's population is at risk of infection with mosquito-borne pathogenic orthoflaviviruses such as DENV. Although the secreted form of the viral NS1 protein has been identified as a major determinant of the pathogenic effects of DENV and related orthoflaviviruses, the exact mechanisms involved in NS1 secretion are poorly understood. Here, we interrogated host factors involved in the secretion of NS1 from infected cells using a customized membrane-trafficking siRNA screen. This revealed three components of the COPI complex that regulate vesicular transport in the early secretory pathway as important factors in NS1 secretion. The involvement of COPI components in NS1 secretion was further validated using wild-type DENV and WNV/KUNV infection, overexpression approaches, and chemical inhibition studies. Together, this study demonstrates the importance of COPI machinery in NS1 secretion and suggests that exploitation of this machinery in NS1 secretion may represent a future target of antiviral drug development.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0096225"},"PeriodicalIF":3.8,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12455993/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959081","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":"Functional orthogonality of parvoviral phospholipase A₂ domains in adeno-associated virus transduction.","authors":"Joshua A Hull, Robert M Fusco, Jeffery Tan, Mark A Ochoa, Aaron Hall, Xinlong Wan, Ezra Loeb, Aravind Asokan","doi":"10.1128/jvi.00799-25","DOIUrl":"10.1128/jvi.00799-25","url":null,"abstract":"<p><p>Dependoparvoviruses, which belong to the family <i>Parvoviridae,</i> are being developed as viral vectors for gene transfer. Notably, different adeno-associated viral (AAV) serotype capsids have been utilized to generate pseudotyped recombinant vectors. While capsid surface regions mediate host cell interactions, buried structural domains have been implicated in parvoviral infectivity and post-entry trafficking. In this regard, the functional diversity of highly conserved group XIII phospholipase A₂ domains (PLA₂) located within the N-terminal capsid domain of different parvoviruses is of particular interest. Here, we developed a massively parallel screen to evaluate a diverse panel of rationally engineered and naturally derived parvoviral PLA₂ domains incorporated within the human isolate, AAV9. <i>In vitro</i> infectious cycling of chimeric virions revealed a functional bias toward parvoviral PLA₂ domains of mammalian and avian origin and decreased preference for PLA₂ domains of insect, ungulate, or metagenomic origin. Notably, wild-type chimeric AAV9 virions carrying avian dependoparvovirus PLA₂ domains demonstrate increased replication over other chimeras. The best-performing recombinant avian/human origin chimera (UNY47950.1/AAV9) shows improved transduction with both single-stranded and self-complementary vector genomes. This observation is accompanied by improved cytoplasmic uptake and nuclear entry of chimeric virions compared to parental AAV9, as evidenced by subcellular fractionation and confocal microscopy. Overall, this study highlights the functional orthogonality of distinct parvoviral PLA₂ domains incorporated into AAV capsids. These chimeric virions present an opportunity to gain deeper insight into the infectious biology of parvoviruses and potentially enable new approaches to improve post-entry trafficking of AAV vectors for gene transfer applications.IMPORTANCEThis study explores the functional overlap of phospholipase domains located within the capsid lumen across the parvovirus family. The findings provide insights into parvovirus-host interactions across different genera within the context of this highly conserved capsid region and underscore its essential role in viral trafficking to the nucleus. Furthermore, incorporation of orthogonal phospholipase domains derived from diverse parvoviral family members may expand the recombinant vector toolkit of adeno-associated viruses for gene transfer applications.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0079925"},"PeriodicalIF":3.8,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12455919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144821903","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 modification to heptad repeat 1 of gp41 improves yield and/or quality of soluble pre-fusion HIV-1 envelope glycoprotein trimers.","authors":"Devidas N Chaturbhuj, Kwinten Sliepen, Albert Cupo, Benjamin Steinberg, Simon Kazimierczyk, Tarek Munawar, Kyle Kramer, Anila Yasmeen, Thales G Andrade, Wen-Hsin Lee, Lara van der Maas, Grace Gibson, Oscar Feliciano, Ivan Del Moral Sanchez, Edith Schermer, Rhianna Bronson, Alison Benner, Madhu Prabhakaran, Rosemarie Mason, P J Klasse, Andrew B Ward, Gabriel Ozorowski, Rogier W Sanders, John P Moore","doi":"10.1128/jvi.00913-25","DOIUrl":"10.1128/jvi.00913-25","url":null,"abstract":"<p><p>Native-like HIV-1 envelope glycoprotein (Env) trimers, exemplified by the SOSIP design, are widely used as immunogens, analytical antigens, and for structural studies. These vaccine research and development programs require trimers that are based on multiple HIV-1 genotypes. While a wide range of protein engineering strategies can produce SOSIP trimers from most Env gene sequences, there are still examples of trimers that are expressed only at impractically low yields or that are unstable. Accordingly, additional protein modifications aimed at overcoming such limitations need to be evaluated. Here, we describe a new heptad repeat 1 modification of gp41, known as dPG, that helps to further stabilize the gp41 component of prototypic and germline-targeting SOSIP trimers in the pre-fusion state and thereby increases post-purification yields substantially. The dPG modification involves a deletion (d) at the highly conserved 566 position that disrupts the heptad repeat and introduces proline (P) and glycine (G) substitutions at positions 567 and 568, respectively. We show that the dPG strategy reinforces previously described stabilization changes in existing SOSIP trimers and can rescue otherwise problematic trimer constructs. The latter includes trimers used to target or analyze human germline antibodies and others derived from the global HIV-1 neutralization panel. In summary, the dPG modification strategy can increase the yield and/or quality of Env trimers that are otherwise difficult to produce.</p><p><strong>Importance: </strong>Stabilized, soluble, pre-fusion SOSIP trimers are widely used in HIV-1 Env vaccine research. Protein engineering techniques have identified multiple ways to stabilize SOSIP trimers from a range of genotypes. However, some SOSIP trimers remain difficult to express at adequate yields and/or purity, so there is a need for additional modifications. Here, we identified a sequence change, designated dPG, to the gp41 subunit that increases the yield and/or quality of various otherwise problematic SOSIP trimers without compromising their antigenicity or structure. This new modification may have general value for HIV-1 vaccine research and development.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0091325"},"PeriodicalIF":3.8,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12455988/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959049","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":"An SRR1 domain-containing protein is required for efficient Orsay virus replication in <i>Caenorhabditis elegans</i>.","authors":"Chika Fujii, David Wang","doi":"10.1128/jvi.00521-25","DOIUrl":"10.1128/jvi.00521-25","url":null,"abstract":"<p><p>Viruses depend on their hosts for completing their life cycle, and a better understanding of virus replication can inform therapeutic strategies. Using the Orsay virus-<i>Caenorhabditis elegans</i> experimental platform, we identified by a forward genetic screen the host gene <i>Y55F3BL.4</i> (renamed <i>viro-9</i>) as a novel host factor critical for Orsay virus replication. Three distinct mutations of <i>viro-9</i> each resulted in a >1,000-fold reduction in Orsay viral load, demonstrating a pro-viral function of <i>viro-9. viro-9</i> had no previously described function in <i>C. elegans</i>, but in the absence of viral infection, deletion of the <i>viro-9</i> locus by CRISPR/Cas9 led to a reduction in brood size and a shortened lifespan. VIRO-9 contains a <i>s</i>ensitivity to <i>r</i>ed light <i>r</i>educed (SRR1) protein domain. While SRR1 domains are present in diverse organisms, including plants, yeast, and mammals, little is known about their function. The <i>Caenorhabditis briggsae</i> ortholog of <i>viro-9</i>, <i>CBG23913</i>, can functionally complement the <i>C. elegans viro-9</i> defect, demonstrating that the pro-viral function of the SRR1 domain is conserved over at least 80 million years of evolution. Furthermore, we identified three conserved amino acid residues within the SRR1 domain that are required for Orsay virus infection. This study provides the first insights into amino acids necessary for functionality of the SRR1 domain and demonstrates the essential role of <i>viro-9</i> in virus infection.IMPORTANCEHost factors required for viral replication could serve as therapeutic targets for various viral species. The <i>Caenorhabditis elegans-</i>Orsay virus experimental system offers a platform for identifying genes important for virus infection in nematodes that may also be important for human-infecting viruses. We determined that <i>viro-9</i>, a previously uncharacterized gene in <i>C. elegans</i> containing the SRR1 domain, is required for Orsay virus replication. The related gene in <i>Caenorhabditis briggsae</i>, a relative of <i>C. elegans</i> that diverged about 80 million years ago, can substitute for <i>viro-9</i>, demonstrating that this protein's ability to promote virus replication is functionally conserved. Because SRR1 domain-containing proteins exist in nematodes, fungi, <i>Drosophila</i>, plants, and mammals, including humans, these proteins could be important for facilitating virus infection in other organisms as well.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0052125"},"PeriodicalIF":3.8,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12455975/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959052","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":"Endogenous human herpesviruses 6A/B.","authors":"Louis Flamand, Jesse Arbuckle, Pascale Bonnafous, Vincent Descamps, Joshua A Hill, Ruth Jarrett, Keith Jerome, Benedikt B Kaufer, Rie Koide, Anthony L Komaroff, Peter Medveczky, Hiroki Miura, Yasuko Mori, Nicholas Parrish, Philip E Pellett, Michael Wood, Tetsushi Yoshikawa, Danielle M Zerr","doi":"10.1128/jvi.01054-25","DOIUrl":"10.1128/jvi.01054-25","url":null,"abstract":"<p><p>Human herpesviruses 6A and 6B (HHV-6A/B) can integrate into the germline, resulting in inherited viral DNA-now proposed to be called \"endogenous HHV-6A/B (eHHV-6A/B).\" Present in 0.2-3% of humans, this integrated DNA is passed to offspring and may reactivate, posing health risks such as angina or lupus. To reduce confusion caused by varied terminology, researchers advocate using \"eHHV-6A/B\" for inherited forms and reserving \"chromosomally integrated\" for somatic integrations only.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0105425"},"PeriodicalIF":3.8,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12456139/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760424","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":"Ubiquitin-specific protease 15 interacts directly with the HSV-1 alkaline nuclease and facilitates viral recombination and replication fork stability.","authors":"Yee Vue, Patrick J Mullon, Alexander Leehangin, Emiliano Maldonado-Luevano, Tyler D Hasselmann, Kavi P M Mehta, Kareem N Mohni","doi":"10.1128/jvi.00893-25","DOIUrl":"10.1128/jvi.00893-25","url":null,"abstract":"<p><p>Herpes simplex virus type 1 replicates in the nucleus of the host cell and utilizes many cellular proteins to facilitate DNA replication. HSV-1 DNA replication is closely linked with homologous recombination, and HSV-1 encodes a two-subunit recombinase consisting of an exonuclease (UL12) and a single-strand DNA-binding protein (ICP8). We identified the cellular deubiquitinating enzyme USP15 as a new UL12-binding partner. USP15 is one of the most enriched proteins on viral DNA and has recently been implicated in regulating cellular homologous recombination. Utilizing isolation of proteins on nascent DNA (iPOND) to compare the proteins on wild-type and UL12-deficient viruses, we observed that USP15 is not recruited to newly replicated DNA in the absence of UL12. We also observed that UL12 and USP15 interact directly <i>in vitro</i> using purified proteins. Together, these data suggest that UL12 directly recruits USP15 to viral DNA. UL12 stimulates a type of homology-directed repair called single-strand annealing (SSA). We generated a USP15 knockout cell line with an integrated GFP-based SSA reporter and observed that UL12 and USP15 both contribute to the maximal induction of SSA. In addition to the reporter cell line, there is a 10-fold reduction in the frequency of marker rescue, and individual replication forks move slower in the absence of USP15. These data support a role for USP15 in facilitating recombination during the virus life cycle and the maintenance of replication fork stability.IMPORTANCEHSV-1 is a ubiquitous pathogen in the global population that causes lifelong latent infection with sporadic reactivation in the host. It has long been appreciated that HSV-1 DNA replication exhibits high rates of recombination and is linked to the host DNA damage response. In this study, we show a novel interaction between UL12, a member of the HSV recombinase, and the deubiquitinating host enzyme USP15. We show that USP15 physically interacts with UL12 and is required for UL12 to maximally stimulate recombination. In the absence of USP15, we also observe an overall reduction in virus growth. This work demonstrated that host proteins facilitate viral-induced recombination. The interaction of USP15 with UL12 represents a potential target for intervention against HSV-1 infection and associated disease.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0089325"},"PeriodicalIF":3.8,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12455970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144873857","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}