Journal of Virology最新文献

{"title":"MADCAP: isolation of novel nAb-naïve AAV capsids from metagenomic data.","authors":"Eugenia Lyashenko, Tess Torregrosa, Alexandra B Ysasi, Jason Wu, Jie Bu, Margaret Hennessy, Youngji Na, Michael J Ryan, Mehmet Takar, Rachna Manek, Joshua A Hull, Edith L Pfister, Christian Mueller, Sourav R Choudhury","doi":"10.1128/jvi.00630-26","DOIUrl":"10.1128/jvi.00630-26","url":null,"abstract":"<p><p>Gene therapy using adeno-associated virus (AAV) vectors offers promising treatment for genetic disorders, but significant limitations restrict clinical application. Current AAV serotypes exhibit strong liver tropism and require high doses for extra-hepatic targeting, and pre-existing antibodies (NAbs) exclude up to 50% of potential patients. Evolutionarily distant isolates can evade neutralization but typically transduce human tissues poorly and require extensive engineering. We developed MADCAP (Metagenomic AAV Discovery and Capsid Annotation Pipeline) to systematically mine metagenomic data for functional, clinically relevant AAV capsids. We hypothesized that these sources might contain capsids that do not circulate widely in humans, can transduce human cells, and avoid neutralization. We screened 4.2 million metagenomic samples and identified 139 novel AAV capsid isolates which were tested for viral capsid assembly, viability, neutralization evasion, and tissue transduction in non-human primates. While natural serotypes (AAV1, AAV2, AAV9) were neutralized at low dilutions of pooled human immunoglobulin (IVIG), 68% of tested MADCAP capsids exhibited minimal to undetectable neutralization even at supra-physiological IVIG concentrations. Systemically delivered MADCAP capsids effectively transduced multiple clinically relevant tissues in non-human primates. Two capsids, MC46 and MC55, demonstrated improved CNS tropism compared to AAV9 while maintaining comparable production yields. In passive transfer studies, MC46 retained full transduction efficiency in the presence of human antibodies, while AAV9 transduction was completely lost. This work establishes metagenomic mining as a powerful tool for accelerating AAV capsid discovery, identifying isolates with favorable tissue tropisms and resistance to broadly neutralizing antibodies.</p><p><strong>Importance: </strong>This work provides proof of concept that potentially clinically relevant AAVs can be isolated from metagenomic data. Our findings lay the groundwork for accelerated discovery of AAV capsids which could potentially increase the accessibility and effectiveness of AAV gene therapy.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0063026"},"PeriodicalIF":4.1,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912437","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":"Megamimivirus double-stranded DNA linear genomes flanked by highly diverse terminal inverted repeats.","authors":"Yucheng Xia, Lanlan Cai, Boyu Ding, Baiyu Su, Rui Zhang","doi":"10.1128/jvi.00825-26","DOIUrl":"10.1128/jvi.00825-26","url":null,"abstract":"<p><p>Giant viruses have fundamentally expanded our understanding of virology by challenging the conventional boundaries of both virion size and genome complexity. However, the scarcity of isolates has left many of their unique biological features unexplored. Here, we report the isolation and characterization of four new giant virus species belonging to the subfamily <i>Megamimivirinae</i>, sampled from distinct environments across China. Among these, Megavirus daqingense is the first giant virus isolated from an oil reservoir; it exhibits virion stability under high salinity, chloroform exposure, and elevated temperatures, suggesting fitness adaptations to subsurface conditions. Using a hybrid sequencing approach that integrates short- and long-read technologies, we assembled complete linear genomes for all four isolates, each flanked by long terminal inverted repeats (TIRs). Comparative genomic and synteny analyses identified 29 distinct TIRs from 46 megamimivirus genomes. Gene content within these TIRs was highly diverse, with no orthologous proteins conserved across all repeats. Furthermore, TIR genes experienced weaker purifying selection than those in non-TIR regions (i.e., the genomic regions excluding the TIRs), consistent with their role as drivers of genome plasticity. Notably, we discovered for the first time that identical tRNA genes are shared between TIRs and non-TIR regions of eukaryotic viruses. Collectively, our work provides insights into the structural and evolutionary complexity of megamimiviruses, revealing TIRs as reservoirs of genetic diversity and hotspots for gene transfer, thereby playing a pivotal role in shaping the dynamic architecture of giant virus genomes.</p><p><strong>Importance: </strong>Terminal inverted repeats (TIRs) are critical structural elements at the termini of linear genomes essential for fundamental processes such as recombination, replication, and integration across diverse organisms. However, the inherent limitations of short-read sequencing technologies have left the complete structure, diversity, and evolutionary significance of long TIRs in giant viruses unexplored. In this study, we leverage hybrid sequencing and comparative genomic analyses to unveil the complexity of TIRs across the subfamily <i>Megamimivirinae</i>. We demonstrate that TIRs are dynamic genomic hotspots characterized by remarkable gene diversity and unexpected conservation of specific tRNA genes. These findings establish TIRs as key drivers of genome plasticity, serving as hotspots for horizontal gene transfer and genetic innovation. By resolving the long-hidden terminal structures of megamimivirus genomes, this work provides a foundational framework for understanding how TIRs shape the evolution of giant viruses and, more broadly, advances our understanding of genome architecture in large DNA viruses.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0082526"},"PeriodicalIF":4.1,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912555","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":"Non-neutralizing antibody responses control acute Crimean-Congo hemorrhagic fever virus infection in naïve mice.","authors":"Kimberly Meade-White, Shanna S Brown, Samantha Ertl, Natalie McCarthy, Thomas Tipih, Heinz Feldmann, David W Hawman","doi":"10.1128/jvi.00987-26","DOIUrl":"10.1128/jvi.00987-26","url":null,"abstract":"<p><p>Crimean-Congo hemorrhagic fever virus (CCHFV) is the cause of a sometimes-severe viral hemorrhagic fever, CCHF. Severe cases of CCHF often have little-to-no CCHFV-specific antibody responses prior to death. However, it is unclear if the failure to mount an antibody response is the cause of a poor outcome or a correlate of a failed host response. Here, we used a mouse-adapted strain of CCHFV (MA-CCHFV) to investigate the requirement of humoral immunity in control of acute CCHFV infection in immunocompetent mice. We found that mice infected with MA-CCHFV develop a rapid non-neutralizing antibody response, consistent with humans infected with CCHFV. Further, we found that the absence of humoral immunity in male but not female mice resulted in near-uniform mortality. Lastly, we determined that complement but not activating Fc-receptors nor the cytoplasmic Fc-receptor tripartite motif containing protein 21 contributed to antibody-mediated control of MA-CCHFV infection. Together, our findings identify rapid humoral immune responses as a critical component of the host response to acute CCHFV infection in naive hosts.IMPORTANCECrimean-Congo hemorrhagic fever virus (CCHFV) is the cause of a serious viral hemorrhagic fever in humans. Severe disease and poor outcomes are correlated with little-to-no CCHFV-specific antibody. However, it is unknown if the lack of CCHFV-specific antibody is a direct cause or merely a correlate of a poor outcome. Here, we investigated the contribution of humoral immunity in control of acute CCHFV infection in naive immunocompetent mice. We found that mice develop a rapid, non-neutralizing antibody response that is crucial for control of the acute infection. Further, we found that loss of complement but not activating Fc receptors or the cytoplasmic Fc receptor TRIM21 worsened disease. Together, our findings suggest that lack of CCHFV-specific antibody responses may directly contribute to poor outcomes in CCHFV-infected humans.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0098726"},"PeriodicalIF":4.1,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148963498","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 factory enters the fray: how mitochondrial protein trafficking shapes the host response to infection.","authors":"Dustin C Hancks, Steven F Baker","doi":"10.1128/jvi.01746-25","DOIUrl":"10.1128/jvi.01746-25","url":null,"abstract":"<p><p>Beyond textbook functions in homeostatic metabolism, mitochondria are now recognized as central coordinators of cell-intrinsic and cell-extrinsic immune responses to infection. Directed trafficking of proteins and other molecules between mitochondria and the rest of the cell underlies a growing catalog of these activities. Some are pro-host; others are antagonized by viral effectors or co-opted by viruses entirely. How host and viral factors rewire the mitochondrial proteome during infection to shape these outcomes remains incompletely understood. The evolutionary history of this system adds another dimension: mitochondria retain biochemical signatures of their α-proteobacterial endosymbiotic origin, and ongoing co-evolution between viral, host, and mitochondrial genomes continues to shape the proteins that traffic to and from the organelle. Using published examples, we highlight general principles, mechanisms, and consequences of host and viral protein localization to and from the mitochondria. To support discovery, we present integrated gene lists identifying host mitochondrial factors with evidence for type I interferon stimulation, interactions with viral proteins, and signatures of positive selection. Together, these resources and the principles within offer a framework for understanding mitochondria not as passive metabolic machinery but as actively contested cellular territory whose protein composition is continuously negotiated between the host and the pathogen.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0174625"},"PeriodicalIF":4.1,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13656305/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148963466","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":"Virus-integrated laboratory models for habitability studies of Enceladus, Europa, and Titan.","authors":"Damara Saggio, S Chantal E Stieber, Jamie C Snyder","doi":"10.1128/jvi.00904-26","DOIUrl":"10.1128/jvi.00904-26","url":null,"abstract":"<p><p>Biogeochemical models have become critical for answering questions about the habitability of ocean worlds, especially that of early Earth. However, when extended to icy moons, experimental biogeochemical systems become especially challenging. Due to less constrained physicochemical parameters extrapolated from former flybys, the most comprehensive approaches could combine experimental and computational models of proposed ocean conditions with microbes present. This minireview makes the case for needing to also include viral/phage interactions with microbial models as a mechanism for maintaining biogeochemical cycling. The viral shunt, or the release and recycling of organic/inorganic matter in aquatic ocean systems via the viral lysis of bacteria and archaea, has proven to be a critical source of carbon/sulfur/iron cycling throughout Earth's oceans. Nonetheless, the viral shunt remains understudied in the realm of other ocean world astrobiology and habitability studies but may provide a mechanism for detection of organics by future missions. The current knowledge of physicochemical conditions on three ocean worlds (Enceladus, Europa, and Titan) is briefly summarized in this work to contextualize examples of Earth-based integrated archaeal viruses (<i>Pyrobaculum</i> filamentous virus, <i>Sulfolobus</i> turreted icosahedral virus, and <i>Methanosarcina</i> spherical virus) that may be suitable for habitability studies for virus-integrated biogeochemical ocean world models.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0090426"},"PeriodicalIF":4.1,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149025317","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":"MOV10 inhibits SADS-CoV replication by enhancing TRIM24-mediated K63-linked TRAF3 ubiquitination, and this inhibition is antagonized by viral N protein.","authors":"Miaomiao Zeng, Dakai Liu, Jiyu Zhang, Liaoyuan Zhang, Hongyan Shi, Xin Zhang, Jianfei Chen, Xiuwen Li, Jialin Zhang, Tingshuai Feng, Xinwei Sun, Junyi Su, Zhaoyang Ji, Li Feng, Da Shi","doi":"10.1128/jvi.01215-26","DOIUrl":"10.1128/jvi.01215-26","url":null,"abstract":"<p><p>The global outbreak of SARS-CoV-2 has resulted in a renewed focus on coronaviruses with the potential for cross-species transmission and mutation risks. In particular, swine acute diarrhea syndrome coronavirus (SADS-CoV), potentially originating from the intermediate horseshoe bat (<i>Rhinolophus affinis</i>), is a novel coronavirus that causes acute diarrhea, vomiting, and high mortality in suckling piglets. Innate immunity plays a crucial role in defending the host against invading pathogens. Previous studies have identified several host factors that inhibit SADS-CoV replication through innate immunity; however, research on SADS-CoV remains insufficient compared to that on other coronaviruses. This study demonstrates that Moloney leukemia virus 10 protein (MOV10) exerts anti-SADS-CoV activity via its N-terminal domain in a helicase activity-independent manner. Mechanistic analysis reveals that MOV10 induces translocation of tripartite motif-containing 24 (TRIM24) from the nucleus to the cytoplasm. The cytoplasmically localized TRIM24 binds to MOV10 and TNF receptor-associated factor 3 (TRAF3) to form a ternary complex. Functional studies demonstrate that MOV10 strengthens the interaction between TRIM24 and TRAF3 in a dose-dependent manner and facilitates TRIM24-mediated K63-linked ubiquitination of TRAF3, thereby activating interferon immune responses. Furthermore, we identify the strategies by which SADS-CoV evades innate immunity. The viral N protein inhibits the antiviral effect of MOV10 by disrupting the interaction between MOV10 and TRAF3 and by promoting K48-linked polyubiquitination of TRAF3, leading to TRAF3 degradation via the ubiquitin-proteasome pathway. Collectively, our findings reveal the role of MOV10 in antiviral immunity and how SADS-CoV evades host immune defense.</p><p><strong>Importance: </strong>Moloney leukemia virus 10 protein (MOV10), a DExD-box RNA helicase, is a known component of cytoplasmic RNA processing centers known as P bodies. As an interferon-stimulated gene (ISG), MOV10 exhibits broad-spectrum antiviral activity against multiple viruses, including SARS-CoV-2, HIV, HSV-1, IAV, and PRRSV. Here, we identify a novel helicase-independent antiviral mechanism of MOV10 against SADS-CoV. In this study, we show that MOV10 bridges TRIM24 and TRAF3 and facilitates K63-linked ubiquitination of TRAF3 independent of its helicase activity. This process strongly amplifies downstream interferon antiviral responses and suppresses viral replication. Furthermore, the SADS-CoV N protein efficiently antagonizes MOV10-mediated immune defense by disrupting the MOV10-TRAF3 interaction and inducing K48-linked ubiquitination and proteasomal degradation of TRAF3. Collectively, this study establishes a previously uncharacterized MOV10-TRIM24-TRAF3 antiviral regulatory axis, which offers new mechanistic insights into how coronaviruses evade host immune defenses.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0121526"},"PeriodicalIF":4.1,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075229","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":"African swine fever virus pMGF110-9L plays a critical role in the integrated stress response and viral pathogenesis.","authors":"Shuai Fan, Han Zhong, Dan Li, Jing Zhang, Yuhang Zhang, Man Hu, Wenrui He, Bo Wan, Zixiang Zhu, Shichong Han, Haixue Zheng, Gaiping Zhang","doi":"10.1128/jvi.01080-26","DOIUrl":"10.1128/jvi.01080-26","url":null,"abstract":"&lt;p&gt;&lt;p&gt;African swine fever virus (ASFV) is the causative agent of ASF, a highly contagious and frequently fatal hemorrhagic disease in domestic swine and wild boars, posing a significant threat to the global pig industry. To ensure successful replication, ASFV may modulate cellular stress mechanisms to hijack the host translation machinery and promote viral factory formation to favor viral protein synthesis and counteract host defenses. However, the interplay between ASFV replication and cellular stress responses has not yet been elucidated, hindering the development of vaccines or therapeutic options. In this study, we dissected how ASFV manipulates the integrated stress response (ISR) to facilitate viral replication and identified the virulence-related factor pMGF110-9L as the strongest activator of ATF4 expression, a key factor downstream of eIF2α phosphorylation during ISR activation. We characterized pMGF110-9L as an endoplasmic reticulum (ER)-localized membrane protein, the expression of which profoundly reorganized the cellular compartments, leading to ER swelling and aggregation. Further proteomic analyses and biochemical experiments revealed that pMGF110-9L is crucial for ASFV-induced ER stress and promotes the activation of the PERK-eIF2α-ATF4, IRE1α-XBP1, and ATF6 branches of the unfolded protein response. Specifically, we demonstrated that pMGF110-9L activates the ISR through the PERK/PKR-eIF2α pathway, leading to viral takeover of the protein synthesis machinery, accompanied by global protein synthesis shutdown and stress granule formation. Furthermore, the transmembrane domain of pMGF110-9L is indispensable for targeting the ER and subsequent stress responses. Overall, these findings inform novel insights into ASFV-host interactions and define a previously uncharacterized role for pMGF110-9L in ASFV pathogenesis.IMPORTANCEAfrican swine fever (ASF), caused by African swine fever virus (ASFV), poses a catastrophic threat to global pork production. The complex pathogenesis and immunoevasion strategies of ASFV have not been clearly elucidated, raising safety concerns regarding modified live virus (MLV) vaccines. Therefore, a better understanding of how ASFV manipulates host responses to establish intracellular conditions favorable for viral replication could provide essential insights into ASFV-host interactions and enable the development of safer and more effective MLV vaccines. In this study, we comprehensively elucidated the relationship between ASFV-encoded proteins and the activation of the integrated stress response. We identified pMGF110-9L as a prominent virulence factor involved in viral takeover of the protein synthesis machinery, accompanied by endoplasmic reticulum (ER) stress, ER-associated aggresome formation, halted host protein translation, and stress granule formation. Importantly, the transmembrane domain of pMGF110-9L was critical for triggering cellular stress mechanisms. This study advances our understanding of ASFV ","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0108026"},"PeriodicalIF":4.1,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148906481","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":"Genetic divergence between reservoir and pre-therapy plasma HIV-1 Env variants does not confer consistent compartment-specific differences in broadly neutralizing antibody sensitivity.","authors":"Siyamthemba Dlamini, Doty Ojwach, Jennifer Giandhari, Bongiwe Ndlovu, Zaza Ndhlovu, Thumbi Ndung'u, Jaclyn Mann","doi":"10.1128/jvi.01151-26","DOIUrl":"10.1128/jvi.01151-26","url":null,"abstract":"<p><p>Broadly neutralizing antibodies (bNAbs) are a promising strategy to target the HIV-1 reservoir, the main barrier to cure. HIV-1 variants may differ in Env sequence and neutralization sensitivity across anatomical compartments. We investigated genetic differences and differences in neutralization sensitivity between Env variants persisting in peripheral blood mononuclear cell (PBMC) and lymph node (LN) reservoirs, and pre-therapy plasma variants. The study included 11 individuals on antiretroviral therapy in Durban, South Africa. Env sequences derived from pre-therapy plasma and from PBMCs and LN reservoirs were assessed for reservoir-specific genetic differences. Recombinant viruses encoding Env variants were generated for six participants and tested for neutralization sensitivity using a panel of nine clinically relevant bNAbs. We observed genetic divergence between compartments, with a median of 6 and 19 amino acid differences between pre-therapy plasma and LN and PBMC reservoirs, respectively. Of these, 63% (LN) and 73% (PBMC) were confirmed by next-generation sequencing to be unique to the reservoir, with few occurring at sites previously associated with altered bNAb sensitivity. Phenotypic analysis revealed no consistent compartment-specific patterns in neutralization sensitivity. CD4-binding site (CD4bs) and gp120-gp41 interface bNAbs showed broad coverage across compartments, while sensitivity to V2 and V3 antibodies was more variable. Although reservoir-derived Env variants show genetic divergence from pre-therapy viruses, this variation is largely not at sites reported to alter bNAb sensitivity and does not translate into consistent compartment-specific differences in bNAb sensitivity. The broad activity of CD4bs and interface-targeting bNAbs across compartments supports their suitability in antibody-based HIV cure strategies.</p><p><strong>Importance: </strong>HIV persists in reservoirs during antiretroviral therapy, preventing a cure. Broadly neutralizing antibodies (bNAbs) are a promising strategy to target these reservoirs, but it is unclear whether viruses in different tissues respond differently to these antibodies. Here, we show that although HIV variants in blood and lymph node reservoirs differ genetically from viruses present before treatment; they do not show consistent changes in antibody sensitivity. Importantly, antibodies targeting the CD4-binding site and the gp120-gp41 interface remained broadly effective across all compartments. These findings suggest that key bNAbs can target HIV reservoirs throughout different body compartments, supporting their use in cure strategies and highlighting the value of combining antibodies to overcome viral diversity.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0115126"},"PeriodicalIF":4.1,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148944491","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":"Changes in the translational landscape during red clover necrotic mosaic virus infection.","authors":"Pulkit Kanodia, Zachary Lozier, Filip Lastovka, David Walker, Peng Liu, Betty Chung, W Allen Miller","doi":"10.1128/jvi.00834-26","DOIUrl":"10.1128/jvi.00834-26","url":null,"abstract":"<p><p>Viruses alter host gene expression to create a proviral environment, while the host simultaneously regulates gene expression to restrict viral spread. Owing to RNA viruses' complete reliance on the host translational machinery, it is important to assess translational control during virus infection. Therefore, we used ribosome profiling (Ribo-seq) paired with RNA-seq to observe how red clover necrotic mosaic virus (RCNMV) infection of Arabidopsis plants alters cellular gene expression at the levels of mRNA abundance and translation efficiency. We determined that at 5 days post-inoculation (dpi), the translational response to RCNMV infection is enriched in genes of the innate immune system. Expression of a tumor necrosis factor receptor-associated factor (TRAF)-like protein, a regulator of development and immune response, was translationally but not transcriptionally upregulated early in systemic infection. By 8 dpi, many pathways were regulated/dysregulated, and unfolded protein response (UPR) genes were transcriptionally upregulated but with reduced translation efficiency. Ribosome profiling of RCNMV RNAs revealed (i) -1 programmed ribosomal frameshifting at 7.5%-8.0%, the first direct measurement of frameshift efficiency in infected cells for any plant virus; (ii) that coat protein is translated at extremely high efficiency, while the RNA-dependent RNA polymerase is translated least efficiently; and (iii) an unexpected extremely strong ribosomal pause site in the open reading frame that encodes the movement protein. To our knowledge, this is the first genome-wide study that assesses the translational control of gene expression in plants infected with a virus from the large and diverse <i>Tombusviridae</i> family.IMPORTANCEPositive-strand RNA viruses usurp the host's translation machinery to synthesize viral proteins. Moreover, translation of host mRNAs is altered by virus infection, both as part of the host immune response and by the virus to inhibit host defenses. To assess all these changes globally, we used ribosome profiling of plants infected with a member of the large and ubiquitous Tombusviridae family. We identified key host genes and pathways that were differentially altered in translation efficiency, giving us an understanding of host responses not detectable by conventional RNA sequencing. Moreover, ribosome profiling revealed (i) the most accurate calculation of the efficiency of ribosomal frameshifting during infection for any plant virus, (ii) the extremely high level of translation of viral coat protein, and (iii) an unexpectedly strong ribosomal pause site in the movement protein gene. This work provides an understanding of a new dimension of gene expression control in plant-virus interactions.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0083426"},"PeriodicalIF":4.1,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149081253","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":"Protein kinase D1 regulates innate immune signaling pathways to promote hepatitis C virus replication.","authors":"Jiyoung Lee, Yu-Chen Chuang, Johanna Ahn Lee, J-H James Ou","doi":"10.1128/jvi.00693-26","DOIUrl":"10.1128/jvi.00693-26","url":null,"abstract":"<p><p>Hepatitis C virus (HCV) has developed multiple means to disrupt host innate immune response to promote its replication. Protein kinase D1 (PKD1) is a serine/threonine kinase involved in cell proliferation and lipid metabolism. By analyzing the effect of PKD1 on HCV replication, we found that HCV activated PKD1 via protein kinase C (PKC) early in infection and induced the cleavage of PKD1 at later timepoints of infection via caspase-3. PKD1 silencing had no effect on HCV entry, but it reduced HCV RNA levels in cells, indicating an important role of PKD1 in promoting HCV replication. PKD1 silencing also induced the expression of interferons (IFNs) and IFN-stimulated genes (ISGs) and augmented the HCV-induced TNF-α expression, which enhanced the IFN response. Interestingly, the induction of inflammasomes was compromised in HCV-infected cells in the absence of PKD1, indicating an important role of PKD1 in promoting the inflammasomal response. Taken together, our results indicated that HCV activated PKD1 to suppress the IFN response and TNF-α signaling and in the meantime induce the inflammasomal response. Our results, thus, revealed an interesting interplay between HCV and host innate immune responses and an important role of PKD1 in this intricate interplay.</p><p><strong>Importance: </strong>Hepatitis C virus (HCV) establishes chronic infection in most patients that it infects, and this chronic infection can lead to severe liver diseases including steatosis, cirrhosis, and hepatocellular carcinoma. PKD1 is a multifunctional protein that regulates lipid metabolism, cell proliferation, and cellular apoptosis. In this report, we investigated the relationship between HCV and PKD1. We found that HCV could activate PKD1 to suppress interferon response and TNF-α signaling to promote its replication and in the meantime enhance the inflammasomal response. These effects of HCV on PKD1 provide important insights for understanding the mechanism of HCV persistence and pathogenesis in patients.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0069326"},"PeriodicalIF":4.1,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912538","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}