Journal of Virology最新文献

{"title":"Neurotropic alphavirus infection induces PARP-1 hyperactivation-mediated energy collapse in motor neurons.","authors":"Rodney Eric Williams, Lisa Pieterse, Swara S Patel, Mathew W McLaren, Matthew J Elrick, Diane E Griffin","doi":"10.1128/jvi.00113-26","DOIUrl":"https://doi.org/10.1128/jvi.00113-26","url":null,"abstract":"<p><p>Motor neurons are highly vulnerable to metabolic stress, yet the mechanisms driving their degeneration during neurotropic alphavirus infections remain unclear. Venezuelan equine encephalitis virus (VEEV) causes motor neuron injury, but the intrinsic pathways underlying this susceptibility are not fully defined. Previous work suggests alphavirus-infected motor neurons may die through caspase-independent mechanisms. Here, we show that VEEV infection induces sustained activation of the DNA repair enzyme poly(ADP-ribose) polymerase-1 (PARP-1), leading to depletion of NAD⁺ and ATP in murine NSC34 motor neuron-like cells and human iPSC-derived motor neurons. These metabolic changes precede mitochondrial depolarization and cell death. Pharmacological inhibition or genetic reduction of PARP-1 partially restores NAD⁺ and ATP and improves cell survival, indicating that PARP-1 hyperactivation directly contributes to energetic collapse and intrinsic motor neuron death. These results identify PARP-1 as a key driver of energy failure during VEEV infection and a potential target to limit neuronal injury in neurotropic viral infections.</p><p><strong>Importance: </strong>Venezuelan equine encephalitis virus (VEEV) is a mosquito-borne pathogen that causes debilitating neurological disease, often targeting motor neurons and leading to permanent injury. While VEEV is known to cause significant damage to these nerve cells, the intrinsic pathways driving this susceptibility are not fully defined. This study demonstrates that VEEV infection induces sustained activation of the DNA repair enzyme poly(ADP-ribose) polymerase-1 (PARP-1), which effectively drains the cell of essential NAD⁺ and ATP. This massive energy failure precedes mitochondrial depolarization and cell death. By showing that pharmacological inhibition or genetic reduction of PARP-1 partially restores energy levels and improves survival in both murine and human motor neurons, these results identify a key driver of cellular collapse. These findings suggest that targeting PARP-1 could provide a potential therapeutic strategy to limit neuronal injury during neurotropic viral infections of the central nervous system.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0011326"},"PeriodicalIF":3.8,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839759","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":"Crystal structure of HERV-K envelope glycoprotein surface subunit.","authors":"Nikos Nikolopoulos, Yorgo Modis","doi":"10.1128/jvi.00195-26","DOIUrl":"https://doi.org/10.1128/jvi.00195-26","url":null,"abstract":"<p><p>The most recently acquired and transcriptionally active family of human endogenous retroviruses (HERVs) is HERV-K. Of the approximately 100 copies of HERV-K in our genome, many retain the potential to proliferate by retrotransposition, express viral proteins, and form functional virus particles. Aberrant expression of the HERV-K envelope glycoprotein (Env) has been associated with cancer and neurodegeneration. Autoantibodies against HERV-K Env have been found in patients with various autoimmune diseases. Here, we report the crystal structure of the Env surface subunit (SU) from HERV-K HML-2, determined at 2.25-Å resolution. The overall fold is somewhat similar to Syncytin-2 SU and distantly related to HIV-1 gp120. The structure contains five disulfides, four N-linked glycans, and two sulfate ions bound to a basic surface groove. Two extended loops form a surface for potential interactions with cell-surface receptors or other cellular factors. The structure also contains three steroid molecules bound to hydrophobic surface patches. This crystal structure provides a platform for future studies to map autoantigenic epitopes, identify small molecules that interfere with HERV-K activity, and extend our mechanistic understanding of retroviruses.IMPORTANCEEight percent to 15% of the human genome consists of endogenous retroviruses and other virus-derived elements inherited from ancestral viral infections. Many endogenous retroviruses from the HERV-K family retain the ability to proliferate across the genome and produce virus-like particles. Aberrant expression of the HERV-K envelope glycoprotein is associated with cancer, neurodegeneration, and autoimmune disease. Here, we report the crystal structure of the HERV-K envelope glycoprotein surface subunit. The structure provides an atomic-level view of the molecular components in HERV-K most likely to trigger autoimmune responses and identifies potential binding sites for drug-like molecules and cell-surface polysaccharides.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0019526"},"PeriodicalIF":3.8,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839787","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":"Pestivirus bovine viral diarrhea virus infection induces ROS-HIF-1a axis-driven glycolytic reprogramming, which increases viral replication by impairing RIG-I-dependent type I interferon response.","authors":"Yuan Li, Jiangfei Zhou, Jing Wang, Kai Yan, Yueming Guan, Mengmeng Wang, Jiayi Xiang, Yimei Liu, Han Yu, Shuo Jia, Wentao Yang, Yigang Xu","doi":"10.1128/jvi.00320-26","DOIUrl":"https://doi.org/10.1128/jvi.00320-26","url":null,"abstract":"<p><p>Pestivirus bovine viral diarrhea virus (BVDV) is a major causative agent of bovine viral diarrhea-mucosal disease, responsible for substantial economic losses in the global cattle industry. BVDV employs sophisticated strategies to evade host antiviral innate immune responses; however, the precise mechanisms remain incompletely understood. In this study, we demonstrate that BVDV infection induces HIF-1α-mediated glycolytic reprogramming, which, in turn, antagonizes the RIG-I/MAVS pathway and suppresses type I interferon (IFN-I) production, thereby facilitating viral replication. We show that BVDV infection activates endoplasmic reticulum stress, leading to a marked increase in reactive oxygen species (ROS) that promote both the expression and stabilization of HIF-1α. As a key regulator of glycolysis, nuclear translocation of HIF-1α upregulates glycolysis-related proteins, including GLUT1, PFKP, HK2, and LDHA, thereby enhancing glycolytic flux. Furthermore, BVDV-induced glycolysis stimulates the formation of an HK2/MAVS/VDAC1 complex, which disrupts RIG-I-MAVS interaction and impairs pathway activation, inhibiting IFN-I production. Additionally, we found that lactate, a glycolytic byproduct, competitively binds to MAVS, impedes its mitochondrial localization, and consequently disrupts the engagement between RIG-I and MAVS. Collectively, our findings reveal a novel mechanism by which BVDV exploits the ROS-HIF-1α-glycolysis axis to attenuate MAVS-mediated antiviral signaling and promote viral replication.</p><p><strong>Importance: </strong>Bovine viral diarrhea virus (BVDV), a member of the genus Pestivirus, is the causative agent of bovine viral diarrhea-mucosal disease, one of the most significant infectious diseases affecting cattle worldwide. BVDV employs diverse mechanisms to evade host innate antiviral immune response, while the precise processes remain incompletely understood. Here, we reveal that BVDV infection drives glycolytic reprogramming through the ROS-HIF-1α axis, leading to the formation of an HK2/MAVS/VDAC1 complex. This complex impairs the interaction between RIG-I and MAVS, resulting in suppressed IFN production. Moreover, we show that lactate, produced via LDHA-mediated glycolysis, binds to MAVS, inhibiting its mitochondrial localization and subsequent association with RIG-I. Together, these mechanisms reveal how BVDV harnesses glycolytic remodeling to dampen RIG-I/MAVS signaling and facilitate viral replication. Our study not only uncovers a potential therapeutic target for combating pestivirus infection but also provides valuable insights into immune evasion strategies shared within the Flaviviridae family, particularly among pestiviruses.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0032026"},"PeriodicalIF":3.8,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839761","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":"Replication-competent SIVcpz CRISPR screen identifies barriers to successful cross-species transmission.","authors":"Qinya Xie, Qingxing Wang, Sabrina Noettger, Guillermo Gosálbez, Annika C Betzler, Meta Volcic, Dorota Kmiec, Stefan Krebs, Alexander Graf, Dila Gülensoy, Gilbert Weidinger, Konstantin M J Sparrer, Frank Kirchhoff","doi":"10.1128/jvi.00314-26","DOIUrl":"https://doi.org/10.1128/jvi.00314-26","url":null,"abstract":"<p><p>Simian immunodeficiency viruses (SIVs) have crossed from apes to humans at least four times, but only one event gave rise to the AIDS pandemic. The host barriers that pandemic HIV-1 group M (<i>major</i>) strains overcame to spread efficiently in humans remain poorly understood. To identify such barriers, we performed CRISPR-Cas9 screens driven by the replication efficiency of SIVcpz, the chimpanzee precursor of HIV-1. Guide RNA libraries targeting more than 500 human genes encoding potential antiviral factors were inserted into the replication-competent SIVcpz MB897 molecular clone, which is phylogenetically closely related to HIV-1 group M strains. Propagation in Cas9-expressing human SupT1 T cells significantly enriched for sgRNAs targeting <i>AXIN1, CEACAM3, CD72, EHMT2, GRN, HMOX1, HMGA1, ICAM2, IFITM2, MEFV, PCED1B, SGOL2, SMARCA4, SUMO1,</i> and <i>TMEM173</i>. These hits only partially overlapped with those identified in analogous HIV-1-based screens, indicating virus-specific restriction profiles. Functional analyses confirmed that IFITM2 (interferon-induced transmembrane protein 2), PCED1B (PC-esterase domain-containing protein 1B), MEFV (Mediterranean fever protein, pyrin/TRIM20), and AXIN1 (Axis inhibition protein 1) restrict replication of the analyzed SIVcpz strains but not HIV-1 group M strains in primary human CD4⁺ T cells. These findings reveal previously unrecognized host factors that limit SIVcpz replication in human cells and highlight barriers that at least some HIV-1 group M strains overcame during adaptation for pandemic spread.</p><p><strong>Importance: </strong>Four independent transmission events of simian immunodeficiency viruses from chimpanzees and gorillas to humans gave rise to human immunodeficiency virus type 1, but only one led to the global AIDS pandemic. Understanding which adaptations allowed the pandemic HIV-1 M strains to spread efficiently in humans remains a key question in virus evolution and public health. In this study, we engineered replication-competent SIVcpz constructs carrying more than 1,500 single-guide RNAs to identify antiviral genes in Cas9-expressing cells. This approach revealed several cellular factors that restrict SIVcpz but not the pandemic HIV-1 M strains analyzed in primary human T cells. These findings provide new insights into antiviral defense mechanisms and the adaptations that most likely contributed to the efficient spread of HIV-1.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0031426"},"PeriodicalIF":3.8,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839781","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":"Bile acids accumulate norovirus-like particles and enhance binding to and entry into human enteric epithelial cells.","authors":"Elin Hahlin, Katarina Danskog, Stefan Nord, Miriam Becker, Stefanie M A Willekens, Carin Wibom, Hugh Tanner, Lars Frängsmyr, Daniel Öhlund, Linda Sandblad, Annasara Lenman, Niklas Arnberg","doi":"10.1128/jvi.00342-26","DOIUrl":"https://doi.org/10.1128/jvi.00342-26","url":null,"abstract":"<p><p>Human norovirus (HuNoV) is a leading cause of acute viral gastroenteritis, but despite high impact on public health and healthcare, the mechanisms of viral attachment to and entry into target cells are not yet fully understood. Recent reports indicate that saliva and bile contribute to the transmission of HuNoV. For example, human bile acids increase cell surface ceramide levels in human enteroids, which improves norovirus entry into cells, resulting in enhanced replication. Bile acids can also interact directly with the norovirus capsid, but it is not known whether bile or other gastrointestinal body fluids directly affect HuNoV attachment to host cells. In this study, we investigated the effects of patient-derived gastric juice, pancreatic juice, and bile on HuNoV GII.4 virus-like particle (VLP) attachment to and entry into a human duodenal cell line, HuTu-80. We show that while gastric juice and pancreatic juice do not affect viral attachment or entry, bile-in particular, hydrophobic bile acids-significantly enhance cellular attachment and subsequent entry of GII.4 VLPs into cells. In addition, we show that hydrophobic bile acids induce the accumulation of viral particles in the vicinity of cells. These results suggest the presence of a new <i>en masse</i> infection mechanism, where bile acids aggregate virions and allow direct and more efficient attachment to and entry into target cells.IMPORTANCEViruses transmitted by the fecal-oral route encounter secreted host factors in gastrointestinal fluids. Some host factors can be exploited by the virus to facilitate infection. Human bile acids indirectly promote norovirus entry into and infection of human enteroids, but the direct effect of bile acids on attachment and uptake, along with the impact of other gastrointestinal fluids, remains unknown. Here, we investigated the direct effects of human body fluids on cellular attachment of norovirus VLPs. We show that human bile and hydrophobic bile acids induce an accumulation of norovirus VLPs, which is associated with significantly enhanced attachment and entry into human duodenal cell lines. These results highlight the differential effects of gastrointestinal body fluids on viral attachment and entry while providing useful information on the complex HuNoV-host interactions that facilitate infection.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0034226"},"PeriodicalIF":3.8,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839517","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":"Correction for Zhou et al., \"Plus-strand RNA viruses hijack Musashi homolog 1 to shield viral RNA from cytoplasmic ribonuclease degradation\".","authors":"Defang Zhou, Menglu Xu, Qingjie Liu, Ruixue Xin, Gege Cui, Longying Ding, Xiaoyang Liu, Xinyue Zhang, Tianxing Yan, Jing Zhou, Shuhai He, Liangyu Yang, Bin Xiang, Ziqiang Cheng","doi":"10.1128/jvi.00333-26","DOIUrl":"https://doi.org/10.1128/jvi.00333-26","url":null,"abstract":"","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0033326"},"PeriodicalIF":3.8,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839730","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":"Novel multigene molecular characterization of avian reovirus strains and associated embryonic pathogenicity.","authors":"Islam Nour, Julia R Blakey, Sonsiray Alvarez-Narvaez, Arun Kulkarni, Quentin D Read, Sujit K Mohanty","doi":"10.1128/jvi.01982-25","DOIUrl":"https://doi.org/10.1128/jvi.01982-25","url":null,"abstract":"<p><p>Avian reovirus (ARV) infection causes a variety of health problems in poultry, including tenosynovitis/arthritis, hepatitis, malabsorption, etc., leading to huge economic losses. Therefore, regular monitoring of ARV strains is crucial for detecting new variants to mitigate clinical disease. Traditional classification approaches have focused primarily on a single gene, σC, which encodes the viral spike protein that elicits neutralizing antibodies. However, additional capsid proteins could play a role by inducing a host antiviral immune response. In this study, the λC, μB, σC, and σB proteins encoded by the L3, M2, S1, and S3 genomic segments, respectively, were analyzed to classify clinical ARV strains with respect to embryonic pathogenicity and genotype-phenotype relationships. Embryo inoculation revealed strain-dependent pathogenicity ranging from the absence of tendon lesions (strain 23-272) to multifocal ulceration with fibrinoheterophilic crusting (22-806) and multifocal necrotizing hepatitis (23-087). Pairwise log-rank and Cox regression tests demonstrated highly significant strain-dependent differences in survival, defining a gradient from rapid embryonic lethality to delayed mortality, with one low-virulence strain exhibiting partial survival. While the λB-σB dual genotyping approach showed insignificant concordance with virulence clusters, a secondary structure-based μB-λC-σC triple model emerged as a better predictor of virulence. Notably, σC exhibited substantial variability in antigenic epitopes, whereas σB remained relatively conserved. These results might explain reduced vaccine efficacy against recent variants and support shifting vaccine design from σC to σB antigen or a combination to achieve broader protection. In conclusion, this multigene, structure-informed framework enhances ARV classification, links genotypes with virulence, and informs improved vaccination strategies.</p><p><strong>Importance: </strong>Avian reovirus (ARV) represents a major threat to poultry health and production, primarily through its association with tenosynovitis/arthritis and the emergence of vaccine-resistant strains driven by high genetic diversity. Effective control requires an ARV classification system beyond traditional schemes based solely on the σC protein, which have proven insufficient to capture pathogenic diversity. We propose a novel, structure-informed triple genotyping approach incorporating the major capsid (μB), the turret (λC), and the virus attachment (σC) proteins. This method improves the prediction of disease severity in chicken embryos while reducing reliance on extensive animal challenge models. Furthermore, our protein-based analysis highlights that the conserved σB protein or a combination of σC & σB protein might be a promising vaccine target capable of providing broader protection across diverse ARV strains, thereby offering new avenues for both improved strain classification and rational vaccine design.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0198225"},"PeriodicalIF":3.8,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839846","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":"A chimeric trivalent Echovirus vaccine designed by loop substitution elicits cross-neutralizing immunity against serotypes 11, 18, and 30.","authors":"Shuai Jiang, Jiaqi Cui, Tao Sun, Jiahuang Li, Heming Li, Tianlun Chen, Jiahui Wu, Zhenhua Zheng, Jianbo Xia, Chunchen Wu, Jie Wu","doi":"10.1128/jvi.00457-26","DOIUrl":"https://doi.org/10.1128/jvi.00457-26","url":null,"abstract":"<p><p>Echoviruses, members of the Enterovirus B genus in the Picornaviridae family, comprise numerous serotypes that frequently cause aseptic meningitis, myocarditis, and severe neonatal infections. The coexistence of multiple antigenically distinct serotypes poses a significant challenge for vaccine development, underscoring the clinical need for a broad-spectrum multivalent vaccine. In this study, we focused on three prevalent serotypes-Echovirus 11 (E11), 18 (E18), and 30 (E30)-as representative models to explore multivalent vaccine design. We first predicted and experimentally identified dominant B-cell epitopes within the VP1 proteins of these viruses. Guided by these analyses, a chimeric trivalent antigen (VP1-III) was rationally constructed by substituting epitope-containing loops from E18 and E30 into the VP1 backbone of E11. Structural modeling confirmed that VP1-III preserved native VP1 conformation while displaying multitype epitopes. Both VP1-III recombinant protein and mRNA-lipid nanoparticle vaccines induced potent immunogenicity in mice, characterized by cross-neutralizing antibodies and Th1-biased cellular responses. These findings support structure-guided epitope integration as a promising strategy for developing broadly protective multivalent Echovirus vaccines.IMPORTANCEEchoviruses cause widespread outbreaks and severe neonatal disease, yet vaccine development remains limited by extensive antigenic diversity among serotypes. Here, we rationally engineered a chimeric trivalent VP1 antigen by grafting dominant epitopes from E11, E18, and E30 through structure-guided loop substitution. Both recombinant protein and mRNA formulations induced robust cross-neutralizing and Th1-biased immune responses in mice, demonstrating that strategic epitope substitution can effectively overcome serotype barriers and providing a promising path toward broad-spectrum Echovirus vaccines.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0045726"},"PeriodicalIF":3.8,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839512","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":"Transcriptional transactivation turns human iPSC-derived macrophages into an adenovirus-producing cell state.","authors":"Maarit Suomalainen, Walther Haenseler, Jonas Kolibius, Andreas Plückthun, Patrick Hearing, Urs F Greber","doi":"10.1128/jvi.00392-26","DOIUrl":"https://doi.org/10.1128/jvi.00392-26","url":null,"abstract":"<p><p>Macrophages conduct first-in-line defense against pathogens, including human adenovirus (AdV). AdVs cause respiratory disease, persist in immune cells, and, upon reactivation, are life-threatening to immunocompromised individuals. Here, our single-cell, single-virus experiments showed that AdV-type-C5 entry into human induced-pluripotent stem cell-derived macrophages is attenuated at cell binding and endosomal escape. A significant fraction (~30%) of the double-stranded viral DNA (vDNA) reaches the cell nucleus; however, it failed to efficiently express the immediate-early viral epigenetic regulator E1A. E1A transcription of silenced vDNA was rescued by E1A expression from a heterologous promoter of a superinfecting AdV, and allowed for full viral replication and progeny formation, even days post-infection, indicating long-lived infectivity of dormant vDNA. Bulk RNA-seq analyses showed that attenuated single AdV-C5 infections upregulated signaling, defense, and proinflammatory genes, whereas productive coinfections upregulated DNA replication and signaling pathways. Together, our data demonstrate that macrophages are a Trojan horse for AdV, notably independent of interferon, raising the possibility that macrophages function as a reservoir for AdV <i>in vivo</i> and reactivate dormant virus via epigenetic signals.</p><p><strong>Importance: </strong>AdV are widespread, cause severe respiratory disease, persist in immune cells, and, upon reactivation, cause life-threatening conditions in immunocompromised individuals. Here, we show that human macrophages are either protected or susceptible to AdV, depending on the cell state, notably in an interferon-independent manner. The decisive cell state switch is the viral immediate-early transcription modulator E1A, which turns a repressive state into a permissive one and allows for the transactivation of dormant AdV-C5 genomes and viral progeny production. The data raise the possibility that macrophages are a hub for AdV persistence and epigenetic reactivation <i>in vivo</i>, in line with the notion that these cells resist immune clearance and serve as reservoirs for HIV, herpesvirus, SARS-CoV-2, or rubella virus infections.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0039226"},"PeriodicalIF":3.8,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147816540","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":"Lock out: targeting TMPRSS2 to block influenza and coronaviruses.","authors":"Lu Zhang, Markus Hoffmann, Stefan Pöhlmann","doi":"10.1128/jvi.00807-25","DOIUrl":"https://doi.org/10.1128/jvi.00807-25","url":null,"abstract":"<p><p>Coronaviruses and influenza A viruses (IAV) can cause severe respiratory disease and have pandemic potential. Both viruses depend on priming of their glycoproteins by host cell proteases for the acquisition of infectivity, and the responsible enzymes represent potential targets for intervention. Initial studies suggested that these viruses may exploit redundant proteolytic systems. However, research conducted over the last two decades has pointed to a key role for a single enzyme in coronavirus and IAV priming, the transmembrane protease serine 2 (TMPRSS2). Interest in TMPRSS2 as a host dependency factor and therapeutic target intensified during the COVID-19 pandemic, prompting extensive investigation into its biology, substrate specificity, and pharmacological inhibition. Here, we review recent efforts to define the role of TMPRSS2 in coronavirus infection and to target this protease for antiviral intervention.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0080725"},"PeriodicalIF":3.8,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147816482","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}