Journal of Virology最新文献

{"title":"Interactions between human immunodeficiency virus and human endogenous retroviruses.","authors":"Mengying Li, Fengting Yu, Baoli Zhu, Jiang Xiao, Chang Yan, Xiaojie Yang, Xuelei Liang, Fang Wang, Hanxi Zhang, Fujie Zhang","doi":"10.1128/jvi.02319-24","DOIUrl":"10.1128/jvi.02319-24","url":null,"abstract":"<p><p>Human immunodeficiency virus (HIV), a retrovirus of the Lentivirus genus, targets CD4⁺ T cells, causing immune dysfunction and AIDS. Approximately 8% of the human genome consists of human endogenous retroviruses (HERVs), ancient retroviral remnants that may interact with HIV. Despite antiretroviral therapy, challenges such as drug resistance, poor immune reconstitution (PIR), and reservoirs remain. This GEM discusses the impact of HIV on HERVs, the potential roles of HERVs in PIR and reservoirs, and provides insights into future research directions.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0231924"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915820/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143365187","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":"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":"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":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915870/pdf/","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":"OA","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":"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":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915834/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tracing more than two decades of Japanese encephalitis virus circulation in mainland China.","authors":"Gairu Li, Xinxin Li, Jie Chen, Phillipe Lemey, Bram Vrancken, Shuo Su, Simon Dellicour, Fabiana Gámbaro","doi":"10.1128/jvi.01575-24","DOIUrl":"10.1128/jvi.01575-24","url":null,"abstract":"<p><p>Japanese encephalitis is a viral disease caused by the Japanese encephalitis virus (JEV), primarily affecting rural areas of Asia and western Pacific region. China remains one of the main epicenters, experiencing a significant burden of human and animal cases despite vaccination efforts. The ecology of this arbovirus is complex, involving <i>Culex</i> mosquitoes as primary vectors, wading birds as natural reservoirs, and pigs as amplifying hosts. Given the virus's epidemiological importance in China, combined with the country's expanding pig farming industry and diverse climates, investigating the virus spread and its environmental drivers is needed to address its persistent burden. In this study, we conducted phylogeographic analyses by combining publicly available JEV envelope gene sequences from China and other regions. Our reconstructions revealed multiple introduction events leading to various circulating JEV clades in China, with one predominant clade. Additionally, our analyses showed a diffusion capacity of JEV exceeding previous estimates for co-circulating arboviruses. These differences could be attributed to pig trade or bird migration, calling for further investigations into the drivers of JEV spread.</p><p><strong>Importance: </strong>Japanese encephalitis virus (JEV) is the cause of Japanese encephalitis, a significant health concern in China. Despite being one of the most studied mosquito-borne viruses, no previous studies have combined genomic and geographic data to investigate the spatial epidemiology and dispersal capacity of the virus. In this study, we analyzed genomic, geographic, and environmental data to trace the dispersal history of JEV in China and explore the environmental factors influencing its distribution. Our findings show that JEV circulates predominantly in areas with higher temperatures, dense human and pig populations, and favorable conditions for <i>Culex</i> mosquitoes. Notably, our analyses showed a higher diffusion capacity of JEV compared to co-circulating viruses, possibly driven by factors like pig trade and bird migration. Our analysis calls for improved genomic surveillance and establishes a baseline for future studies on the effects of climate change, agricultural practices, and bird migration on JEV circulation.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0157524"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143408581","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":"PLSCR1 suppresses SARS-CoV-2 infection by downregulating cell surface ACE2.","authors":"Ruiyi Ma, Xinyi Zhang, Ruonan Li, Xiaojing Dong, Wenjing Wang, Qi Jiang, Xia Xiao, Yujin Shi, Lan Chen, Tian Zheng, Zichun Xiang, Lili Ren, Zhuo Zhou, Xiaobo Lei, Jianwei Wang","doi":"10.1128/jvi.02085-24","DOIUrl":"10.1128/jvi.02085-24","url":null,"abstract":"<p><p>Type I interferons exert their antiviral effects against SARS-CoV-2 by inducing the expression of interferon-stimulated genes (ISGs), including but not limited to LY6E, CH25H, IFITM2/3, and IFIH1. However, the antiviral effect and underlying mechanisms of action of most ISGs in SARS-CoV-2 infection are not yet fully understood. By screening 109 ISG-knockout cell lines, we identify that phospholipid scramblase 1 (PLSCR1), an interferon-inducible protein, acts as a crucial restriction factor against SARS-CoV-2 infection. Cells lacking PLSCR1 are highly susceptible to SARS-CoV-2 infection. Conversely, overexpression of PLSCR1 inhibits SARS-CoV-2 infection. Depletion of PLSCR1 enhances cellular entry of both pseudotyped and authentic SARS-CoV-2. Mechanistically, PLSCR1 inhibits SARS-CoV-2 entry by specifically downregulating plasma membrane expression of ACE2, the virus's receptor, without affecting the overall levels of ACE2 within the cell. As such, we unraveled previously unappreciated mechanisms by which PLSCR1 exerts its restrictive effect on SARS-CoV-2. These data provide new insights into the interplay between host innate antiviral immunity and SARS-CoV-2 and shed light on novel antiviral therapeutics.</p><p><strong>Importance: </strong>Phospholipid scramblase 1 (PLSCR1) has been identified as a critical host restriction factor against SARS-CoV-2 infection. In this study, we demonstrated that PLSCR1 inhibited SARS-CoV-2 entry by downregulating the plasma membrane expression of ACE2, the primary receptor for viral entry. Our findings elucidate a novel host-pathogen interaction that not only deepens our understanding of the innate immune response to SARS-CoV-2 but offers potential strategies for therapeutic interventions against COVID-19.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0208524"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915802/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143408651","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":"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":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915788/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>In situ</i> structures of the contractile nanomachine myophage Mu in both its extended and contracted states.","authors":"Junquan Zhou, Liwen Wang, Hao Xiao, Wenyuan Chen, Zhonghua Liu, Jingdong Song, Jing Zheng, Hongrong Liu","doi":"10.1128/jvi.02056-24","DOIUrl":"10.1128/jvi.02056-24","url":null,"abstract":"<p><p>Myophage Mu is a representative of contractile nanomachines with a simple tail baseplate. It has the capacity to infect a range of intestinal bacteria and has extensive applications in genetic engineering research. Nevertheless, a comprehensive understanding of the entire structure and contractile mechanisms of Mu remains elusive. Using cryo-electron microscopy (cryo-EM), we resolved the asymmetric structures of Mu in both its extended and contracted states, the latter of which lacked the tail baseplate, at near-atomic resolutions. We built the atomic models for the extended Mu, encompassing the head, the connector complex, the tail, and the simple baseplate. It is noteworthy that we identified the position and structure of the tail tube initiator protein gp43 (referred to as the DNA circularization protein). The protein gp43 plays a crucial role not only in the baseplate assembly and DNA circularization but also in stabilizing the wedge-hub connection and mediating tail contraction. Except for the baseplate structure, the structural comparison of Mu in its extended and contracted states revealed that only the tail sheath protein gp39 and the C-terminus of the tail terminator protein gp37 undergo notable conformational changes to accommodate the tail contraction, whereas the remaining protein components remained unchanged. Our structures exhibited conserved properties among the majority of myophages, thereby providing valuable insights into the contraction mechanisms across myophages and contractile injection systems (CISs).</p><p><strong>Importance: </strong>Despite extensive study, the asymmetric structures of phage Mu, a highly effective transposable myophage, remain unknown. In this study, we present the high-resolution structures of Mu in both its extended and contracted states. The comparison of the two structures allows for the illustration of detailed conformational changes of the head-to-tail complex during the process of tail contraction. The contraction mechanism of Mu is highly conserved and widely adapted to all contractile nanomachines that share common structural features with Mu.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0205624"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483574","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":"mRNA vaccine-induced SARS-CoV-2 spike-specific IFN-γ and IL-2 T-cell responses are predictive of serological neutralization and are transiently enhanced by pre-existing cross-reactive immunity.","authors":"Philip Samaan, Chapin S Korosec, Patrick Budylowski, Serena L L Chau, Adrian Pasculescu, Freda Qi, Melanie Delgado-Brand, Tulunay R Tursun, Geneviève Mailhot, Roya Monica Dayam, Corey R Arnold, Marc-André Langlois, Justin Mendoza, Thomas Morningstar, Ryan Law, Erik Mihelic, Salma Sheikh-Mohamed, Eric Yixiao Cao, Nimitha Paul, Anjali Patel, Keelia Quinn de Launay, Jamie M Boyd, Alyson Takaoka, Karen Colwill, Vitaliy Matveev, Feng Yun Yue, Allison McGeer, Sharon Straus, Anne-Claude Gingras, Jane M Heffernen, Mario Ostrowski","doi":"10.1128/jvi.01685-24","DOIUrl":"10.1128/jvi.01685-24","url":null,"abstract":"<p><p>The contributions of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells to vaccine efficacy and durability are unclear. We investigated relationships between mRNA vaccine-induced spike-specific interferon- gamma (IFN-γ) and interleukin-2 (IL-2) T-cell responses and neutralizing antibody development in long-term care home staff doubly vaccinated with BNT162b2 or mRNA-1273. The impacts of pre-existing cross-reactive T-cell immunity on cellular and humoral responses to vaccination were additionally assessed. Mathematical modeling of the kinetics of spike-specific IFN-γ and IL-2 T-cell responses over 6 months post-second dose was bifurcated into recipients who exhibited gradual increases with doubling times of 155 and 167 days or decreases with half-lives of 165 and 132 days, respectively. Differences in kinetics did not correlate with clinical phenotypes. Serological anti-spike IgG, anti-receptor binding domain (RBD) IgG, anti-spike IgA, and anti-RBD IgA antibody levels otherwise decayed in all participants with half-lives of 63, 57, 79, and 46 days, respectively, alongside waning neutralizing capacity (<i>t</i>_1/2 = 408 days). Spike-specific T-cell responses induced at 2-6 weeks positively correlated with live viral neutralization at 6 months post-second dose, especially in hybrid immune individuals. Participants with pre-existing cross-reactive T-cell immunity to SARS-CoV-2 exhibited greater spike-specific T-cell responses, reduced anti-RBD IgA antibody levels, and a trending increase in neutralization at 2-6 weeks post-second dose. Non-spike-specific T-cells predominantly targeted SARS-CoV-2 non-structural protein at 6 months post-second dose in cross-reactive participants. mRNA vaccination was lastly shown to induce off-target T-cell responses against unrelated antigens. In summary, vaccine-induced spike-specific T-cell immunity appeared to influence serological neutralizing capacity, with only a modest effect induced by pre-existing cross-reactivity.</p><p><strong>Importance: </strong>Our findings provide valuable insights into the potential contributions of mRNA vaccine-induced spike-specific T-cell responses to the durability of neutralizing antibody levels in both uninfected and hybrid immune recipients. Our study additionally sheds light on the precise impacts of pre-existing cross-reactive T-cell immunity to severe acute respiratory syndrome coronavirus 2 on the magnitude and kinetics of cellular and humoral responses to vaccination. Accordingly, our data will help optimize the development of next-generation T cell-based coronavirus vaccines and vaccine regimens to maximize efficacy and durability.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0168524"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915849/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066083","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":"YTHDF1 and YTHDC1 m⁶A reader proteins regulate HTLV-1 <i>tax</i> and <i>hbz</i> activity.","authors":"Emily M King, Amanda Midkiff, Karsyn McClain, Sanggu Kim, Amanda R Panfil","doi":"10.1128/jvi.02063-24","DOIUrl":"10.1128/jvi.02063-24","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus responsible for adult T-cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a progressive neurodegenerative disease. Regulation of viral gene expression plays a key role in viral persistence and pathogenesis. However, the molecular mechanisms underlying this fine-tuned regulation remain poorly understood. Little is known regarding RNA chemical modifications of HTLV-1 RNA and how these affect viral biology and disease development. Post-transcriptional chemical modification of RNA is common in eukaryotes, with N&lt;sup&gt;6&lt;/sup&gt;-methyladenosine (m&lt;sup&gt;6&lt;/sup&gt;A) being the most prevalent. In this study, we investigated the role of m&lt;sup&gt;6&lt;/sup&gt;A RNA modifications on HTLV-1 gene expression. Using MeRIP-Seq, we mapped the sites of m&lt;sup&gt;6&lt;/sup&gt;A modification to the 3' end of the viral genome. We found HTLV-1 RNA, as well as viral oncogene transcripts &lt;i&gt;tax&lt;/i&gt; and &lt;i&gt;hbz&lt;/i&gt;, contained m&lt;sup&gt;6&lt;/sup&gt;A modifications. m&lt;sup&gt;6&lt;/sup&gt;A-depletion in HTLV-1-transformed cells decreased sense-derived viral genes (&lt;i&gt;Tax, Gag,&lt;/i&gt; and &lt;i&gt;Env&lt;/i&gt;) and increased antisense-derived &lt;i&gt;Hbz&lt;/i&gt; expression. &lt;i&gt;Tax&lt;/i&gt; and &lt;i&gt;hbz&lt;/i&gt; transcripts were bound by reader proteins YTHDF1 and YTHDC1 in a panel of HTLV-1 T-cell lines. Using expression vectors and shRNA-mediated knockdown, we found that YTHDF1 had opposing effects on viral gene expression, decreasing sense-derived viral genes and increasing antisense-derived &lt;i&gt;Hbz&lt;/i&gt;. Upon further study, the YTHDF1 effects on &lt;i&gt;tax&lt;/i&gt; abundance were dependent on &lt;i&gt;tax&lt;/i&gt; m&lt;sup&gt;6&lt;/sup&gt;A deposition. The nuclear m&lt;sup&gt;6&lt;/sup&gt;A reader protein YTHDC1 affected the abundance of both sense- and antisense-derived viral transcripts and specifically enhanced the nuclear export of &lt;i&gt;tax&lt;/i&gt; transcript. Collectively, our results demonstrate global m&lt;sup&gt;6&lt;/sup&gt;A levels and m&lt;sup&gt;6&lt;/sup&gt;A reader proteins YTHDF1 and YTHDC1 regulate HTLV-1 gene expression.IMPORTANCEHuman T-cell leukemia virus type 1 (HTLV-1) persistence and pathogenesis are controlled through tight regulation of viral gene expression. The fate of RNA can be controlled by epigenetic modifications that impact gene expression without altering the DNA sequence. Our study details the impact of N6-methyladenosine (m&lt;sup&gt;6&lt;/sup&gt;A) RNA chemical modifications on HTLV-1 gene expression. We found that reductions in global m&lt;sup&gt;6&lt;/sup&gt;A levels affected viral gene expression, decreasing &lt;i&gt;Tax&lt;/i&gt; and other sense-derived viral genes, whereas increasing the antisense-derived &lt;i&gt;Hbz&lt;/i&gt;. Our results suggest the oncogenic viral transcripts, &lt;i&gt;tax&lt;/i&gt; and &lt;i&gt;hbz&lt;/i&gt;, are m&lt;sup&gt;6&lt;/sup&gt;A-modified in cells. We found that these viral RNA modifications are interpreted by reader proteins YTHDF1 and YTHDC1, which dictate the fate of the viral RNA. Understanding HTLV-1 RNA chemical modifications offers potential insights into novel therapeutic strategies for HTLV-1-associated disease","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0206324"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915865/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189005","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":"Conventional and antibody-enhanced DENV infection of human macrophages induces differential immunotranscriptomic profiles.","authors":"Céline S C Hardy, Adam D Wegman, Mitchell J Waldran, Gary C Chan, Adam T Waickman","doi":"10.1128/jvi.01962-24","DOIUrl":"10.1128/jvi.01962-24","url":null,"abstract":"<p><p>Dengue virus (DENV) is a mosquito-borne flavivirus which coexists as four genetically and immunologically distinct serotypes (DENV-1 to -4). In secondary heterologous DENV infection, pre-existing immunity is believed to contribute to severe disease through antibody-dependent enhancement (ADE). Although the elevated pathology observed in ADE conditions has been described, the cell-intrinsic mechanisms governing this process remain unclear. Using single-cell RNA sequencing (scRNAseq), we investigated the transcriptomic profiles of human monocyte-derived macrophages infected by DENV-2 in ADE compared to conventional infection conditions. Unsupervised analysis of scRNAseq data enabled the identification of two distinct cell populations in a heterogeneous cell culture, likely representing infected and bystander/uninfected cells. Differential gene expression and ingenuity pathway analyses revealed a number of significantly upregulated and downregulated genes and gene networks between cells infected by ADE compared to conventional infection. Specifically, these pathways indicated mechanisms such as suppressed interferon signaling and inflammatory chemokine transcription in cells infected via ADE. Further analysis revealed that transcriptomic changes were independent of viral RNA within infected cells, suggesting that the observed changes are reflective of cell-intrinsic responses and not simply a function of per-cell viral burden. The interpreted \"bystander\" cell population also demonstrated distinct profiles in ADE conditions, indicating an immunologically activated phenotype enriched for the expression of gene networks involved with protein translation, cytokine production, and antigen presentation. Together, these findings support the concept that DENV infection via ADE induces a qualitatively different transcriptomic response in infected cells, contributing to our understanding of ADE as a mechanistic driver of disease and pathogenesis.IMPORTANCEDengue virus (DENV) is a mosquito-borne human pathogen with a significant and growing global health burden. Although correlates of severe dengue disease are poorly understood, pre-existing immunity to DENV has been associated with severe disease risk and known to contribute to an alternative route of viral entry termed antibody-dependent enhancement (ADE). Using single-cell RNA sequencing, we identified distinct transcriptomic processes involved in antibody-mediated DENV entry compared to conventional receptor-mediated entry. These data provide meaningful insight into the discrete processes contributing to DENV pathogenesis in ADE conditions.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0196224"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189655","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}