Journal of Virology最新文献

{"title":"FBXO45 restricts HIV-1 replication by inducing SQSTM1/p62-mediated autophagic degradation of Tat.","authors":"Mingxiu Xu, Haobo Hu, Weijing Yang, Jiaxiang Zhang, Hong Wang, Wenyan Zhang, Chen Huan","doi":"10.1128/jvi.01912-24","DOIUrl":"https://doi.org/10.1128/jvi.01912-24","url":null,"abstract":"<p><p>As a key regulator of human immunodeficiency virus type 1 (HIV-1) transcription, Tat plays an essential role in viral replication and latency, making it a promising target for designing viral control strategies. Identifying host factors that modulate Tat and exploring the underlying mechanisms will benefit our understanding of HIV-1 transcriptional regulation and provide valuable insights into Tat-based therapeutic strategies. Here, by employing the TurboID approach, we discovered high-affinity binding between FBXO45 and Tat. Our findings demonstrate that FBXO45 negatively regulates Tat by promoting Tat ubiquitination and directing it to autophagic degradation. Autophagic degradation of Tat has been reported, but the specific underlying mechanisms remain unidentified. We elucidated this issue by providing evidence that FBXO45-mediated Tat polyubiquitination is an essential prerequisite for this process. Silencing of FBXO45 leads to a deficiency of autophagy receptor SQSTM1/p62 to bind and facilitate the autophagic degradation of Tat. Our results further underscore the crosstalk between post-translational modifications of Tat by demonstrating that the phosphorylation site of the Tat S62 residue is required for ubiquitination induced by FBXO45. Furthermore, in the context of the regulation of HIV-1, FBXO45 inhibits viral replication and maintains the latency of HIV-1 by suppressing viral transcription. Importantly, FBXO45 overexpression significantly attenuated viral rebound after antiretroviral therapy withdrawal. In summary, our findings suggest a novel role for FBXO45 in regulating HIV-1 replication by inducing the ubiquitination and SQSTM1/p62-dependent autophagic degradation of Tat. Considering the indispensable role of Tat in the regulation of HIV-1 replication and reactivation, FBXO45 may be a potential target for therapeutic intervention against HIV-1.IMPORTANCEHIV-1 Tat plays an indispensable role in regulating viral transcription and is a promising target for achieving a functional cure for AIDS. Identifying the host factors that modulate Tat expression could benefit the development of anti-HIV-1 strategies targeting Tat. Using TurboID assay, we identified a significant interaction between FBXO45 and Tat. Functionally, FBXO45 ubiquitinates and directs Tat for SQSTM1/p62-mediated autophagic degradation, thereby effectively restricting HIV-1 replication and maintaining HIV-1 latency by suppressing Tat-dependent viral transcription. These findings uncover a novel role for FBXO45 in regulating Tat and broaden our understanding of the host mechanisms involved in Tat processing.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0191224"},"PeriodicalIF":4.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399540","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":"Evolution of ubiquitin, cytoskeleton, and vesicular trafficking machinery in giant viruses.","authors":"Sangita Karki, Frank O Aylward","doi":"10.1128/jvi.01715-24","DOIUrl":"https://doi.org/10.1128/jvi.01715-24","url":null,"abstract":"<p><p>Members of the phylum <i>Nucleocytoviricota</i>, which include \"giant viruses\" known for their large physical dimensions and genome lengths, are a diverse group of dsDNA viruses that infect a wide range of eukaryotic hosts. The genomes of nucleocytoviruses frequently encode eukaryotic signature proteins (ESPs) such as RNA- and DNA-processing proteins, vesicular trafficking factors, cytoskeletal components, and proteins involved in ubiquitin signaling. Despite the prevalence of these genes in many nucleocytoviruses, the timing and number of gene acquisitions remains unclear. While the presence of DNA- and RNA-processing proteins in nucleocytoviruses likely reflects ancient gene transfers, the origins and evolutionary history of other proteins are largely unknown. In this study, we examined the distribution and evolutionary history of a subset of viral-encoded ESPs (vESPs) that are widespread in nucleocytoviruses. Our results demonstrate that most vESPs involved in vesicular trafficking were acquired multiple times independently by nucleocytoviruses at different time points after the emergence of the eukaryotic supergroups, while viral proteins associated with cytoskeletal and ubiquitin system proteins exhibited a more complex evolutionary pattern exhibited by both shallow and deep branching viral clades. This pattern reveals a dynamic interplay between the co-evoluton of eukaryotes and their viruses, suggesting that the viral acquisition of many genes involved in cellular processes has occurred both through ancient and more recent horizontal gene transfers. The timing and frequency of these gene acquisitions may provide insight into their role and functional significance during viral infection.IMPORTANCEThis research is pertinent for understanding the evolution of nucleocytoviruses and their interactions with eukaryotic hosts. By investigating the distribution and evolutionary history of viral-encoded eukaryotic signature proteins, the study reveals gene transfer patterns, highlighting how viruses acquire genes that allow them to manipulate host cellular processes. Identifying the timing and frequency of gene acquisitions related to essential cellular functions provides insights into their roles during viral infections. This work expands our understanding of viral diversity and adaptability, contributing valuable knowledge to virology and evolutionary biology, while offering new perspectives on the relationship between viruses and their hosts.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0171524"},"PeriodicalIF":4.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391131","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":"Diversities of African swine fever virus host-virus dynamics revealed by single-cell profiling.","authors":"Xiaoyang Zhao, Yanyan Zhang, Hanying Jia, Lin Lv, Md Asif Ahsan, Xudong Fu, Rongliang Hu, Zhiqiang Shen, Ning Shen","doi":"10.1128/jvi.02035-24","DOIUrl":"https://doi.org/10.1128/jvi.02035-24","url":null,"abstract":"<p><p>African swine fever virus (ASFV) causes epidemics with high mortality; however, effective vaccines and therapies remain missing. Here, we depict a temporal single-cell landscape of primary porcine alveolar macrophages (PAMs) exposed to three different virulent ASFV strains <i>in vitro</i>. We found that attenuated and low-virulence ASFV strains tend to exhibit higher viral loads than highly virulent strain, which may result from upregulated RNA polymerase subunit genes expression. On the host side, our study highlights the IRF7-mediated positive feedback loop to the activation of the interferon signaling pathway in cells exposed to attenuated and low virulent ASFV strains. Moreover, we unraveled the PAMs populations marked by expressions of the <i>IFI16</i> and <i>CD163</i>, respectively, which produce high levels of interferon-stimulated genes (ISGs) and IL18 to regulate the host response to different virulent ASFV strains. Collectively, our data provide insights into the complex host-virus interactions with various ASFV strain infections, which may shed light on the development of effective antiviral strategies.IMPORTANCEThere is still no available research on the temporal transcriptional profile of host cells exposed to different virulent ASFV strains at the single-cell level. Here, we first profiled the temporal viral and host transcriptomes in PAMs exposed to high virulent, attenuated virulent, and low virulent ASFV strains. Our analysis revealed that attenuated and low-virulence ASFV strains tend to exhibit higher viral loads than highly virulent strains, which may result from upregulated RNA polymerase subunit genes expression. We also found a positive feedback loop of the interferon signaling pathway mediated through IRF7 and identified the populations of PAMs marked by <i>IFI6</i> and <i>CD163</i>, respectively, which produce high levels of ISGs and <i>IL18</i> to regulate host response to different virulent ASFV strains. Our study delineated a comprehensive single-cell landscape of host-virus dynamics across ASFV strains with different virulences and would provide an important resource for future research.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0203524"},"PeriodicalIF":4.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391125","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":"Activation of CXCR3⁺ Tfh cells and B cells in lymph nodes during acute HIV-1 infection correlates with HIV-specific antibody development.","authors":"Julie L Mitchell, Supranee Buranapraditkun, Pierre Gantner, Hiroshi Takata, Kenneth Dietze, Kombo F N'guessan, Justin Pollara, Junsuke Nohara, Roshell Muir, Eugene Kroon, Suteeraporn Pinyakorn, Nicha Tulmethakaan, Sopark Manasnayakorn, Suthat Chottanapund, Pattarawat Thantiworasit, Peeriya Prueksakaew, Nisakorn Ratnaratorn, Suwanna Puttamaswin, Bessara Nuntapinit, Lawrence Fox, Elias K Haddad, Dominic Paquin-Proulx, Praphan Phanuphak, Carlo P Sacdalan, Nittaya Phanuphak, Jintanat Ananworanich, Denise Hsu, Sandhya Vasan, Guido Ferrari, Nicolas Chomont, Lydie Trautmann","doi":"10.1128/jvi.01532-24","DOIUrl":"https://doi.org/10.1128/jvi.01532-24","url":null,"abstract":"<p><p>Lymph node T follicular helper (Tfh) cells and germinal center (GC) B cells are critical to generate potent antibodies but are rarely possible to study in humans. To understand how Tfh/GC B-cell interactions during acute HIV-1 infection (AHI) impact the generation of HIV-specific antibodies, we performed a unique cross-sectional analysis of inguinal lymph node biopsies taken prior to antiretroviral therapy (ART) initiation in AHI. Although total Tfh and GC B cell frequencies did not change during AHI, increased frequencies of proliferating Th1-like CXCR3⁺ Tfh, CXCR3⁺ non-GC B cells, and total CXCR3⁺ GC B cells correlated with gp120-specific IgG antibody levels in AHI. Frequencies of proliferating CXCR3⁺ Tfh in AHI also correlated with gp120-specific IgG antibody levels after 48 weeks of ART, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and increased antibody binding to infected cells after ART. Importantly, while beneficial for antibody development, CXCR3⁺ Tfh cells were also infected by HIV-1 at higher frequencies than their CXCR3^- counterparts and may contribute to the initial dissemination of HIV-1 in follicles. Together, these data suggest that activation of CXCR3⁺ Tfh cells is associated with induction of the germinal center response and subsequent antibody development, making these cells an important target for future therapeutic interventions.</p><p><strong>Importance: </strong>Early initiation of antiretroviral therapy (ART) is important to limit the seeding of the long-lasting HIV-1 reservoir; however, it also precludes the development of HIV-specific antibodies that can help control the virus if ART is stopped. Antibody development occurs within germinal centers in the lymph node and requires activation of both antigen-specific B cells and T follicular helper cells (Tfh), a specialized CD4⁺ cell that provides B cell help. To understand how early ART initiation may prohibit antibody development, we analyzed the frequencies and activation status of Tfh and B cells in lymph node biopsies collected in the different stages of acute HIV-1 infection. Our data suggest that decreased antibody development after early ART initiation may be due to limited germinal center development at the time of treatment and that new interventions that target activation of CXCR3⁺ Tfh may be beneficial to increase long-term HIV-specific antibody levels.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0153224"},"PeriodicalIF":4.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391109","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":"Differential mosaicism of recombinant foot-and-mouth disease viruses resulting from heterologous superinfection of cattle.","authors":"Carolina Stenfeldt, Ian H Fish, Monica Rodriguez-Calzada, Gisselle Medina, Juergen A Richt, Jonathan Arzt","doi":"10.1128/jvi.02213-24","DOIUrl":"https://doi.org/10.1128/jvi.02213-24","url":null,"abstract":"<p><p>Evidence from both field and experimental studies suggests that recombination is a common feature in the evolution of foot-and-mouth disease virus (FMDV). Recent studies have demonstrated that heterologous superinfection of cattle persistently infected with FMDV leads to rapid generation of inter-serotypic recombinant viruses in the upper respiratory tract mucosa. The current study demonstrates that the order of exposure to FMDV strains A24 Cruzeiro and O1 Manisa substantially influenced the patterns of mosaicism of resultant recombinants. FMDV recombinants were isolated from oropharyngeal fluid samples from 7 of 12 cattle following heterologous superinfection at 21 days post-initial infection. There was no apparent competitive advantage of either parental virus. However, recombinant viruses recovered from six of seven animals had gained, or regained through multiple recombination events, the capsid-coding sequence of FMDV O1 Manisa despite the presence of high titers of neutralizing antibodies against that virus. Additionally, a sub-genomic region of high amino acid diversity, spanning the 3' portion of 3A through 3B, was derived from FMDV A24 in most of the recovered recombinants. Despite the frequent recovery of FMDV recombinants from the upper respiratory tract of superinfected animals, there was no detection of recombinant viruses in blood or lesions in the subset of animals that developed clinical foot-and-mouth disease during superinfection. Overall, these findings confirm the high frequency at which FMDV recombination occurs when persistently infected carrier cattle are exposed to a heterologous virus and reaffirm that superinfection of carriers should be considered as a source of FMDV genetic diversity in endemic regions.IMPORTANCEFoot-and-mouth disease virus (FMDV) is a pathogen of domestic livestock with profound global socioeconomic impacts. FMDV causes a subclinical persistent infection in ruminant hosts, such as cattle, during which the animals may become sequentially infected by heterologous variants of the virus. Our previous works have demonstrated that such superinfections frequently lead to emergence of novel recombinant virus variants in the upper respiratory tracts of infected animals. This current investigation demonstrates that the order in which the animals are exposed to two different viruses substantially influences the structure of resultant recombinant genomes and confirms the frequency at which FMDV recombination occurs following heterologous superinfection of persistently infected FMDV carriers.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0221324"},"PeriodicalIF":4.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391124","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":"Begomovirus capsid proteins interact with cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase of its whitefly vector and modulate virus retention within its vector.","authors":"Saptarshi Ghosh, Banani Mondal, Ola Jassar, Murad Ghanim, Saurabh Gautam, Vamsidhar Reddy Netla, Rajagopalbabu Srinivasan","doi":"10.1128/jvi.02172-24","DOIUrl":"https://doi.org/10.1128/jvi.02172-24","url":null,"abstract":"<p><p>Begomoviruses are whitefly-transmitted ss-DNA viruses that infect dicotyledonous plants and contribute to major economic losses to global crop production. Invasion and establishment of an aggressive cryptic species of <i>Bemisia tabaci</i>, known as the B cryptic species, has severely constrained vegetable production in the southeastern and southwestern United States. Disruption of genes/pathways critical for whitefly-mediated transmission can be effective for the management of begomoviruses. In this study, yeast two-hybrid (Y2H)-based screening of <i>B. tabaci</i> cDNA library identified a cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase-4 (PDE4) of the whitefly as an interacting partner with capsid proteins (CPs) of old- and new-world begomoviruses. Interactions of PDE4 with begomovirus CPs were validated by glutathione-S-transferase (GST) pull-down assay and co-immunolocalization in whitefly midgut. The PDE4 family of enzymes hydrolyzes cAMP and regulates intracellular cAMP levels. This study conclusively proves that acquisition of begomoviruses downregulates the expression of PDE4 (mRNA and protein) resulting in elevated cAMP levels within the whitefly. The role of cAMP post virus acquisition is further elucidated wherein elevation of cAMP by chemical inhibition or gene (PDE4) silencing resulted in increased retention and transmission of begomoviruses. Similarly, decreased cAMP levels resulted in reduced begomovirus retention. The results of this study demonstrate that whitefly-mediated transmission of begomoviruses is regulated by intracellular cAMP by unknown mechanisms.</p><p><strong>Importance: </strong>Begomoviruses, transmitted by the sweetpotato whitefly (<i>Bemisia tabaci</i> Gennadius), are the causal agents of many economically important plant virus diseases. Lack of host plant resistance against begomoviruses, high whitefly abundance, and whitefly's ability to develop insecticide resistance rapidly often render the commonly used management practice ineffective. This study demonstrates how begomovirus retention within whitefly and its transmission can be modulated by altering cyclic adenosine monophosphate (cAMP) expression of its insect vector. Naturally occurring bio-pesticides that target insect cAMPs are known. Our findings can lead to alternative strategies for the management of begomoviruses by targeting whitefly cAMP using chemicals, botanicals, or RNAi-based insecticides.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0217224"},"PeriodicalIF":4.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391112","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":"IFI16 recruits HDAC1 and HDAC2 to deacetylate the Kaposi's sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA), facilitating latency.","authors":"Anandita Ghosh, Jeffrey Britto, Bala Chandran, Arunava Roy","doi":"10.1128/jvi.01549-24","DOIUrl":"https://doi.org/10.1128/jvi.01549-24","url":null,"abstract":"<p><p>IFI16 (interferon-γ-inducible protein 16) is an innate-immune DNA sensor that detects viral dsDNA in the nucleus. It also functions as an antiviral restriction factor, playing a crucial role in regulating the latency/lytic balance of several herpesviruses, including Kaposi's sarcoma-associated herpesvirus (KSHV). We previously demonstrated that IFI16 achieves this by regulating the deposition of H3K9me3 marks on the KSHV genome. Here, we explored whether IFI16 impacts the KSHV latency/lytic balance through additional mechanisms. Our analysis of the IFI16 interactome revealed that IFI16 binds to the class-I HDACs, HDAC1 and HDAC2, and recruits them to the KSHV major latency protein, latency-associated nuclear antigen (LANA). Previous reports have suggested that LANA undergoes lysine acetylation through unknown mechanisms, which results in the loss of its ability to bind to the KSHV transactivator protein (RTA) promoter. However, how the LANA acetylation-deacetylation cycle is orchestrated and what effect this has on KSHV gene expression remains unknown. Here, we demonstrate that LANA, by default, undergoes post-translational acetylation, and during latency, IFI16 interacts with this acetylated LANA and recruits HDAC1/2 to it. This keeps LANA in a deacetylated form, competent in binding and repressing lytic promoters. However, during lytic reactivation, IFI16 is degraded via the proteasomal pathway, leading to the accumulation of acetylated LANA, which cannot bind to the RTA promoter. This results in the de-repression of the RTA and, subsequently, other lytic promoters, driving reactivation. These findings shed new light on the role of IFI16 in KSHV latency and suggest that KSHV utilizes the cellular IFI16-HDAC1/2 interaction to facilitate its latency.</p><p><strong>Importance: </strong>Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic γ-herpesviruses etiologically associated with several human malignancies, including Kaposi's sarcoma, primary effusion B-cell lymphoma, and multicentric Castleman's disease. Understanding the molecular mechanisms governing the establishment and maintenance of latency in γ-herpesviruses is crucial because latency plays a pivotal role in oncogenesis and disease manifestation post-infection. Here, we have elucidated a new mechanism by which IFI16, a previously discovered antiviral restriction factor, is hijacked by KSHV to recruit class-I HDACs on latency-associated nuclear antigen (LANA), resulting in the latter's deacetylation. The acetylation status of LANA is critical for KSHV latency because it governs LANA's binding to the KSHV replication and transcription activator (RTA) promoter, an immediate-early gene crucial for lytic reactivation. Depletion of IFI16 results in the accumulation of acetylated LANA, which is incapable of maintaining latency. These newly discovered interactions between IFI16 and LANA and between IFI16 and HDAC1/2 enhance our understanding of KSHV latency regulations.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0154924"},"PeriodicalIF":4.0,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382817","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":"Generation of RNA aptamers against chikungunya virus E2 envelope protein.","authors":"Kaku Goto, Ryo Amano, Akiko Ichinose, Akiya Michishita, Michiaki Hamada, Yoshikazu Nakamura, Masaki Takahashi","doi":"10.1128/jvi.02095-24","DOIUrl":"10.1128/jvi.02095-24","url":null,"abstract":"<p><p>Nucleic acid aptamers are a promising drug modality, whereas the generation of virus-neutralizing aptamers has remained difficult due to the lack of a robust system for targeting the viral particles of interest. Here, we took advantage of our latest platform technology of Systematic Evolution of Ligands by EXponential enrichment (SELEX) with virus-like particles (VLPs) and targeted chikungunya virus (CHIKV) as a model, the pathogenic reemerging virus with an unmet need for control. The identified aptamer against CHIKV-VLPs, Apt#1, and its truncated derivatives showed neutralizing activity with nanomolar IC50 values in a cell-based assay system using a pseudoviral particle of CHIKV (CHIKVpp). An antiviral-based chemical genetics approach revealed significant competition of Apt#1 with suramin, a reported interactant with domain A of the E2 envelope protein (E2DA), in both CHIKVpp and surface plasmon resonance (SPR) analyses, predicting E2DA to be the Apt#1 interface. In addition, Apt#1 interfered with the attachment of CHIKVpp, collectively suggesting its property as an attachment inhibitor via E2DA of CHIKV. Thus, the generation of the VLP-targeted aptamers proved to contribute to anti-CHIKV strategies and confirmed the utility of the platform as a novel and viable option for the development of neutralizing agents against viral particles of interest.IMPORTANCEOur latest SELEX technology using VLPs has generated aptamers that bind the native conformation of the incorporated envelope protein and achieve the virus binding and neutralizing effects. Indeed, the aptamer-probed target E2DA is a representative neutralization site on the surface of the viral particle, validating the utility of the VLP-driven procedure. Simultaneously, the enhanced antiviral effects of the aptamer in combination with approved drugs using the CHIKVpp assay with human cells indicated potential therapeutic strategies that are expected to help address unmet needs in CHIKV control. The robust affinity of the aptamer to viral particles demonstrated by SPR analysis can also lead to conjugates with antivirals as guiding molecules and aptasensors for diagnostic tools. Overall, our VLP-based method provided anti-CHIKV as well as a versatile platform applicable to other emerging and reemerging viruses, in preparation for outbreaks with the need for rapid development of antiviral strategies as next-generation theranostics.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0209524"},"PeriodicalIF":4.0,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382759","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":"Seneca Valley virus 3C protease cleaves HDAC4 to antagonize type I interferon signaling.","authors":"Zijian Li, Jingjing Yang, Ruiyi Ma, Shijie Xie, Dan Wang, Rong Quan, Xuexia Wen, Jue Liu, Jiangwei Song","doi":"10.1128/jvi.02176-24","DOIUrl":"https://doi.org/10.1128/jvi.02176-24","url":null,"abstract":"<p><p>Seneca Valley virus (SVV) is a newly identified pathogen that poses a notable threat to the global pig industry. SVV has evolved multiple strategies to evade host antiviral innate immune responses. However, the underlying molecular mechanisms have not yet been fully elucidated. Histone deacetylases (HDACs) have been shown to function as host antiviral innate immune factors. In this study, we examined the mechanisms underlying SVV evasion of host innate immunity and found that SVV infection induced degradation and cleavage of HDAC4. Ectopic expression of HDAC4 suppressed SVV replication, whereas siRNA-mediated knockdown of HDAC4 enhanced SVV replication. Further studies showed that the viral 3C protease (3C^pro) degraded HDAC4 in a protease activity- and caspase pathway-dependent manner. In addition, 3C^pro cleaved HDAC4 at Q599, which blocked its ability to limit viral replication. We also found that HDAC4 interacted with the SVV viral RNA-dependent RNA polymerase 3D and induced its proteasomal degradation. The cleaved HDAC4 products did not block SVV replication or induce 3D degradation and did not induce type I interferon (IFN) activation and expression of IFN-stimulated genes (ISGs). Collectively, these findings identified HDAC4 as an antiviral factor with effects against SVV infection and provided mechanistic insights into how SVV 3C^pro antagonizes its function, which has implications for viral evasion of innate immunity.</p><p><strong>Importance: </strong>Seneca Valley virus (SVV) is an emerging pathogen that causes vesicular disease in pigs and poses a threat to the pork industry. Histone deacetylases (HDACs) are important in the regulation of innate immunity. However, little is known about their roles in SVV infection. Our results revealed HDAC4 as an anti-SVV infection factor that targets the viral RNA-dependent RNA polymerase, 3D, for degradation. The SVV proteinase 3Cpro targets HDAC4 for degradation and cleavage, and cleavage of HDAC4 abrogated its antiviral effect. HDAC4 promotes type I interferon (IFN) signaling, and SVV 3Cpro-mediated cleavage of HDAC4 antagonized induction of type I IFN and interferon-stimulated genes (ISGs). Our findings reveal a novel molecular mechanism by which SVV 3Cpro counteracts type I IFN signaling by targeting HDAC4.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0217624"},"PeriodicalIF":4.0,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382819","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 conserved lysine/arginine-rich motif is essential for the autophagic degradation of potyviral 6K1 protein and virus infection.","authors":"Weiyao Hu, Changhui Deng, Li Qin, Peilan Liu, Linxi Wang, Xaioqing Wang, Wei Shi, Asma Aziz, Fangfang Li, Xiaofei Cheng, Aiming Wang, Zhaoji Dai, Xiaohua Xiang, Hongguang Cui","doi":"10.1128/jvi.02183-24","DOIUrl":"10.1128/jvi.02183-24","url":null,"abstract":"<p><p>Potyviruses possess one positive-sense single-stranded RNA genome, mainly dependent on polyprotein processing as the expression strategy. The resulting polyproteins are proteolytically processed by three virus-encoded proteases into 11 or 12 mature proteins. One such factor, 6 kDa peptide 1 (6K1), is an understudied viral factor. Its function in viral infection remains largely mysterious. This study is to reveal part of its roles by using pepper veinal mottle virus (PVMV) as the model. Alanine substitution screening analysis revealed that 15 of 17 conserved residues across potyviral 6K1 sequences are essential for PVMV infection. However, 6K1 protein is less accumulated in virus-infected cells, although P3-6K1 and 6K1-CI junctions are efficiently processed by NIa-Pro for its release, indicating that 6K1 undergoes a self-degradation event. Mutating the cleavage site to prevent NIa-Pro processing abolishes viral infection, suggesting that the generation of 6K1 along with its degradation might be important for viral multiplication. We corroborated that cellular autophagy is engaged in 6K1's degradation. Individual engineering of the 15 6K1 variants into PVMV allows their expression along with viral infection. Five of such variants, D30A, V32A, K34A, L36A, and L39A, significantly interfere with viral infection. The five residues are enclosed in a conserved lysine/arginine-rich motif; four of them appear crucial in engaging autophagy-mediated self-degradation. Based on these data, we envisaged a scenario which potyviral 6K1s interact with an unknown anti-viral component to be co-degraded by autophagy to promote viral infection.IMPORTANCE<i>Potyvirus</i> is the largest genus of plant-infecting RNA viruses, which encompasses socio-economically important virus species, such as <i>Potato virus Y</i>, <i>Plum pox virus</i>, and <i>Soybean mosaic virus</i>. Like all picorna-like viruses, potyviruses express their factors mainly via polyprotein processing. Theoretically, viral factors P3 through CP, including 6K1, should share an equivalent number of molecules. The 6K1 is small in size (~6 kDa) and conserved across potyviruses but less accumulated in virus-infected cells. This study demonstrates that cellular autophagy is engaged in the degradation of 6K1 to promote viral infection. In particular, we found a conserved lysine/arginine-rich motif in 6K1s across potyviruses that is engaged in this degradation event. This finding reveals one facet of a small protein that helps understand the pro-viral role of cellular autophagy in viral infection.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0218324"},"PeriodicalIF":4.0,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382745","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}