Journal of Virology最新文献

{"title":"SARS-CoV-2 cellular coinfection is limited by superinfection exclusion.","authors":"Anna Sims, Daniel J Weir, Sarah J Cole, Edward Hutchinson","doi":"10.1128/jvi.02077-24","DOIUrl":"https://doi.org/10.1128/jvi.02077-24","url":null,"abstract":"<p><p>The coinfection of individual cells is a requirement for exchange between two or more virus genomes, which is a major mechanism driving virus evolution. Coinfection is restricted by a mechanism known as superinfection exclusion (SIE), which prohibits the infection of a previously infected cell by a related virus after a period of time. SIE regulates coinfection for many different viruses, but its relevance to the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was unknown. In this study, we investigated this using a pair of SARS-CoV-2 variant viruses encoding distinct fluorescent reporter proteins. We show for the first time that SARS-CoV-2 coinfection of individual cells is limited temporally by SIE. We defined the kinetics of the onset of SIE for SARS-CoV-2 in this system, showing that the potential for coinfection starts to diminish within the first hour of primary infection and then falls exponentially as the time between the two infection events is increased. We then asked how these kinetics would affect the potential for coinfection with viruses during a spreading infection. We used plaque assays to model the localized spread of SARS-CoV-2 observed in infected tissue and showed that the kinetics of SIE restrict coinfection-and therefore sites of possible genetic exchange-to a small interface of infected cells between spreading viral infections. This indicates that SIE, by reducing the likelihood of coinfection of cells, likely reduces the opportunities for genetic exchange between different strains of SARS-CoV-2 and therefore is an underappreciated factor in shaping SARS-CoV-2 evolution.</p><p><strong>Importance: </strong>Since SARS-CoV-2 first emerged in 2019, it has continued to evolve, occasionally generating variants of concern. One of the ways that SARS-CoV-2 can evolve is through recombination, where genetic information is swapped between different genomes. Recombination requires the coinfection of cells; therefore, factors impacting coinfection are likely to influence SARS-CoV-2 evolution. Coinfection is restricted by SIE, a phenomenon whereby a previously infected cell becomes increasingly resistant to subsequent infection. Here we report that SIE is activated following SARS-CoV-2 infection and reduces the likelihood of coinfection exponentially following primary infection. Furthermore, we show that SIE prevents coinfection of cells at the boundary between two expanding areas of infection, the scenario most likely to lead to recombination between different SARS-CoV-2 lineages. Our work suggests that SIE reduces the likelihood of recombination between SARS-CoV-2 genomes and therefore likely shapes SARS-CoV-2 evolution.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0207724"},"PeriodicalIF":4.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674120","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":"Efficacy of parainfluenza virus 5 (PIV5)-vectored intranasal COVID-19 vaccine as a single dose primer and booster against SARS-CoV-2 variants.","authors":"Ashley C Beavis, Zhuo Li, Kelsey Briggs, María Cristina Gingerich, Elizabeth R Wrobel, Maria Najera, Dong An, Nichole Orr-Burks, Jackelyn Murray, Preetish Patil, Jiachen Huang, Jarrod Mousa, Linhui Hao, Tien-Ying Hsiang, Michael Gale, Stephen B Harvey, S Mark Tompkins, Robert Jeffrey Hogan, Eric R Lafontaine, Hong Jin, Biao He","doi":"10.1128/jvi.01989-24","DOIUrl":"10.1128/jvi.01989-24","url":null,"abstract":"<p><p>Immunization with COVID-19 vaccines has greatly reduced COVID-19-related deaths and hospitalizations from SARS-CoV-2 infection, but waning immunity and the emergence of variants capable of immune escape indicate the need for annual vaccine updates or development of different SARS-CoV-2 vaccine platforms. Parainfluenza virus 5 (PIV5)-vectored intranasal COVID-19 vaccine with the ancestral spike (S) protein (CVXGA1) has been shown to be a promising next-generation COVID-19 vaccine preclinically and is currently being evaluated in humans. This work investigates the immunogenicity and efficacy of CVXGA1 and other PIV5-vectored vaccine candidates expressing additional SARS-CoV-2 nucleoprotein (N) antigen or SARS-CoV-2 variant S proteins of beta, delta, gamma, and omicron variants against homologous and heterologous challenges in hamsters. A single intranasal dose of CVXGA1 induces neutralizing antibodies (nAbs) against SARS-CoV-2 WA1 (ancestral), delta variant, and omicron variant and protects against both homologous and heterologous virus challenges. Compared to mRNA COVID-19 vaccine, neutralizing antibody titers induced by CVXGA1 were well maintained over time. When administered as a booster following two doses of an mRNA COVID-19 vaccine, PIV5-vectored vaccines expressing the S protein from WA1 (CVXGA1), delta, or omicron variants generate higher levels of cross-reactive nAbs than three doses of mRNA vaccine. Our data indicate that an intranasal PIV5-vectored COVID-19 vaccine can serve as a booster vaccine against emerging variants.</p><p><strong>Importance: </strong>With emerging new variants of concern (VOC), SARS-CoV-2 continues to be a major threat to human health. Approved COVID-19 vaccines have been less effective against these emerging VOCs. This work demonstrates the protective efficacy and strong boosting effect of an intranasal viral-vectored vaccine against SARS-CoV-2 variants in hamsters. Our intranasal vaccine can act as an effective booster for individuals already 58 vaccinated against SARS-CoV-2.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0198924"},"PeriodicalIF":4.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674033","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":"Development of ferret immune repertoire reference resources and single-cell-based high-throughput profiling assays.","authors":"Evan S Walsh, Kui Yang, Tammy S Tollison, Sujatha Seenu, Nicole Adams, Guilhem Zeitoun, Ifigeneia Sideri, Geraldine Folch, Hayden N Brochu, Hsuan Chou, Sofia Kossida, Ian A York, Xinxia Peng","doi":"10.1128/jvi.00181-25","DOIUrl":"https://doi.org/10.1128/jvi.00181-25","url":null,"abstract":"<p><p>Domestic ferrets (<i>Mustela putorius furo</i>) are important for modeling human respiratory diseases. However, ferret B and T cell receptors have not been completely identified or annotated, limiting immune repertoire studies. Here, we performed long-read transcriptome sequencing of ferret splenocyte and lymph node samples to obtain over 120,000 high-quality full-length immunoglobin (Ig) and T cell receptor (TCR) transcripts. We constructed a complete reference set of the constant regions of ferret Ig and TCR isotypes and chain types. We also systematically annotated germline Ig and TCR variable (V), diversity (D), joining (J), and constant (C) genes on a recent ferret reference genome assembly. We designed new ferret-specific immune repertoire profiling assays by targeting positions in constant regions without allelic diversity across 11 ferret genome assemblies and experimentally validated them using a commercially compatible single-cell-based platform. These improved resources and assays will enable future studies to fully capture ferret immune repertoire diversity.IMPORTANCEDomestic ferrets (<i>Mustela putorius furo</i>) are an increasingly common model organism to study human respiratory diseases such as influenza infections. However, researchers lack ferret-specific reagents and resources to study the immune system and immune response in ferrets. In this study, we developed comprehensive ferret immune repertoire reference resources and assays, which will enable more accurate analyses of the ferret immune system in the future.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0018125"},"PeriodicalIF":4.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674017","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":"Hairpin inserts in viral genomes are stable when they conform to the thermodynamic properties of viral RNA substructures.","authors":"Chanyong Jang, Jason M Needham, Philip Z Johnson, Feng Gao, Anne E Simon","doi":"10.1128/jvi.01919-24","DOIUrl":"https://doi.org/10.1128/jvi.01919-24","url":null,"abstract":"<p><p>Virus-induced gene silencing (VIGS) allows for the rapid targeting of gene expression and has been instrumental in characterizing plant genes. However, foreign sequences inserted into VIGS vectors are rarely maintained for unknown reasons. Citrus yellow vein-associated umbravirus-like virus (CY1) with its solved secondary structure was converted into a VIGS vector to determine why simple hairpins inserted into non-functional, single-stranded locations are not maintained. When CY1 contained foreign hairpins with thermodynamic properties (positional entropy and/or ΔG) differing from those of natural CY1 hairpins, deletions arose within a few weeks of infecting <i>Nicotiana benthamiana</i>. In contrast, duplication and insertion of four natural CY1 hairpins (up to 200 nt) into the same locations were retained until plant senescence. Hairpins containing similar conformations and thermodynamic properties as natural hairpins were also retained, as were hairpins that shared thermodynamic properties but were conformationally distinct. By predicting and modulating these thermodynamic properties, a hairpin was retained by CY1 for at least 30 months in citrus. These findings strongly suggest that RNA viruses have evolved to contain substructures with specific thermodynamic properties, and hairpins containing these properties are stable when inserted into non-functional regions of the genome, opening up VIGS for long-lived trees and vines.</p><p><strong>Importance: </strong>Plus-strand RNA plant viruses are used as tools to introduce small interfering RNAs (siRNAs) into laboratory plants to target and silence genes. However, virus-induced gene silencing (VIGS) vectors engineered to contain foreign hairpins or other sequences for siRNA generation are not stable, and the foreign sequences are rapidly lost. We found that foreign sequences are not maintained in an umbravirus-like VIGS vector (CY1) because their physical properties conflict with the innate properties of the CY1 genome's substructures (i.e., hairpins). When natural CY1 hairpins were duplicated and inserted into locations where previous inserts were rapidly lost, the hairpins were now stable as were unrelated hairpins with the same physical properties. By mimicking the physical properties of the viral genome, one insert was stable for over 30 months. These results suggest that RNA viral genomes have evolved to have specific physical properties, and these properties appear to be similar for other plus-strand RNA viruses.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0191924"},"PeriodicalIF":4.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674100","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 parainfluenza virus 5 (PIV5)-vectored intranasal SARS-CoV-2 vaccine (CVXGA1) elicits protective and long-lasting immunity in nonhuman primates.","authors":"Ashley C Beavis, Peng Xiao, Maria Cristina Gingerich, Kelsey Briggs, Geng Li, Elizabeth W Howerth, Maria Najera, Dong An, Jiachen Huang, Jarrod Mousa, S Mark Tompkins, Gina Kim, Stephen B Harvey, Robert Jeffrey Hogan, Eric R Lafontaine, Francois J Villinger, Hong Jin, Biao He","doi":"10.1128/jvi.01990-24","DOIUrl":"https://doi.org/10.1128/jvi.01990-24","url":null,"abstract":"<p><p>Waning immunity from approved COVID-19 vaccines and emerging variants of SARS-CoV-2 necessitate the need to develop alternative COVID-19 vaccines for improved durability and broader protection. This work investigates the efficacy and mucosal, humoral, and cellular immunogenicity of intranasal, parainfluenza virus 5 (PIV5)-vectored COVID-19 vaccine CVXGA1 in an African green monkey (AGM) nonhuman primate model. A single intranasal dose of CVXGA1 induced robust and sustained humoral and cellular immune responses in AGMs and protected against SARS-CoV-2 ancestral WA1 strain and alpha variant challenge infection in the respiratory tracts as demonstrated by lack of viral load and greatly decreased histopathology. Mucosal IgA antibodies were detected in the upper and lower respiratory tracts of immunized AGMs. CVXGA1-vaccinated AGMs maintained serum anti-S IgG and IgA antibody titers for over 245 days. S-specific CD4⁺ and CD8⁺ T cells producing predominantly IFN-γ, TNF-α, MIP-β, and CD107α cytokines peaked on day 28 and could be detected on day 180 by intracellular cytokine staining of peripheral blood mononuclear cells (PBMC). IL13-secreting CD4⁺ and CD8⁺ T cells were minimally detected, indicative of a dominant type 1 immune response. These data supported the clinical evaluation of CVXGA1 intranasal COVID-19 vaccine. These data demonstrate that intranasal immunization with CVXGA1 induces long-lasting protective SARS-CoV-2 S-specific mucosal, humoral, and cellular responses in AGMs.IMPORTANCEThe continued threat of SARS-CoV-2 indicates the need for a novel vaccine that induces long-lasting mucosal, cellular, and humoral immunity, as well as block transmission. This work demonstrates that intranasal, PIV5 viral-vectored SARS-CoV-2 vaccine CVXGA1 induces mucosal immunity and long-lasting cellular and humoral immunity that protects African green monkeys from SARS-CoV-2 challenge. The ability of our intranasal vaccine to elicit long-lasting mucosal, cellular, and humoral immunity against SARS-CoV-2 indicates great promise of the PIV5-vectored COVID-19 vaccine for further clinical development.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0199024"},"PeriodicalIF":4.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674012","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":"Effect of host telomerase inhibition on human cytomegalovirus.","authors":"Chloe M Cavanaugh, Cora N Betsinger, Nicole Katchur, Sherry Zhang, Karen Yang, Maciej Nogalski, Ileana M Cristea, Daniel Notterman","doi":"10.1128/jvi.01578-24","DOIUrl":"10.1128/jvi.01578-24","url":null,"abstract":"<p><p>Treatment options remain limited for human cytomegalovirus (HCMV). Host telomerase has been implicated in the pathogenesis and oncogenesis of multiple herpesviruses, most recently including HCMV. In this study, we investigated the effect of telomerase inhibition on HCMV replication, as well as the mechanism of the interaction between HCMV and host telomerase <i>in vitro</i>. We found that lytic HCMV infection increases host telomerase activity, at least in part, through modulation of hTERT expression during earlier phases of the HCMV replication cycle. We found telomerase inhibition strongly reduced viral titer for two HCMV strains in a dose-specific manner. Both post-translational pharmaceutical telomerase inhibition and siRNA-mediated knockdown of hTERT reduce HCMV yield. Telomerase inhibition results in both reduction of viral gene and protein expression across the HCMV replication cycle, and suppressed viral genome replication and viral infectivity, suggesting interference with at least early steps of the HCMV viral life cycle. Altogether, our findings indicate telomerase plays an important, perhaps non-canonical role in lytic HCMV infection which includes the support of viral replication and infectivity.</p><p><strong>Importance: </strong>Human cytomegalovirus (HCMV) seroprevalence and morbidity in immunocompromised patients and neonates infected <i>in utero</i> remain high globally. Host telomerase has been implicated in the success of multiple infection-induced pathologies, including the success of both lytic infection and oncogenesis in certain herpesviruses. The results of this study suggest a similar biologically important role for host telomerase in lytic HCMV infection. Furthermore, these results may provide the potential for a novel, adjunctive anti-viral treatment for HCMV infection as well as insight into the viral products likely to be involved with HCMV regulation of telomerase.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0157824"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189658","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":"RAF1 promotes successful human cytomegalovirus replication and is regulated by AMPK-mediated phosphorylation during infection.","authors":"Diana M Dunn, Ludia J Pack, Joshua C Munger","doi":"10.1128/jvi.01866-24","DOIUrl":"10.1128/jvi.01866-24","url":null,"abstract":"<p><p>RAF1 is a key player in growth factor receptor signaling, which has been linked to multiple viral infections, including human cytomegalovirus (HCMV) infection. Although HCMV remains latent in most individuals, it can cause acute infection in immunocompromised populations, such as transplant recipients, neonates, and cancer patients. Current treatments are suboptimal, highlighting the need for novel therapies. Multiple points in the growth factor signaling pathway are important for HCMV infection, but the relationship between HCMV and RAF1, a component of the mitogen-activated protein kinase (MAPK) cascade, is not well understood. The AMP-activated protein kinase (AMPK) is a known regulator of RAF1, and AMPK activity is induced by HCMV infection, which is important for productive HCMV replication. Our data indicate that HCMV infection induces AMPK-specific changes in RAF1 protein phosphorylation, including increasing phosphorylation at RAF1-Ser621, a known AMPK phospho-site, which results in increased binding to the 14-3-3 scaffolding protein, an important aspect of RAF1 protein activation. Inhibition of RAF1, either pharmacologically or via shRNA or CRISPR-mediated targeting, inhibits viral replication and spread in both fibroblasts and epithelial cells. Collectively, our data indicate that HCMV infection and AMPK activation modulate RAF1 activity, which is important for viral replication.</p><p><strong>Importance: </strong>Human cytomegalovirus (HCMV) infection is a widespread infection impacting approximately 60-90% of the global population. Although latent in healthy individuals, acute infection in immunocompromised populations, such as neonates, transplant recipients, and cancer patients, can result in retinal and gastrointestinal problems, hearing loss, and even death. Current antivirals are suboptimal due to the development of viral resistance or toxicity in patients, highlighting the need for novel treatments. Our research suggests a new potential target, RAF1, which is a regulator of cellular growth and proliferation. We find that RAF1 is phosphorylated by AMP-activated protein kinase, and that inhibition of RAF1 negatively impacts viral infection. Furthermore, drugs currently used to treat certain cancers also inhibit RAF1 and may have an additional anti-HCMV therapeutic effect in HCMV-susceptible cancer patients.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0186624"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915854/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189714","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":"Characterization and therapeutic potential of newly isolated bacteriophages against <i>Staphylococcus</i> species in bovine mastitis.","authors":"Jae-Hyun Cho, Gyu Min Lee, Seyoung Ko, Youngju Kim, Donghyuk Kim","doi":"10.1128/jvi.01901-24","DOIUrl":"10.1128/jvi.01901-24","url":null,"abstract":"<p><p>Bovine mastitis, primarily caused by <i>Staphylococcus aureus</i>, significantly affects the dairy industry by reducing milk production and quality. The rise of antibiotic-resistant bacteria has prompted the need for alternative treatments. The three newly isolated bacteriophages, OPT-SA02, OPT-SC01, and OPT-SX11, were isolated from chicken fecal and sewage samples in South Korea. These bacteriophages were characterized via physiological and genomic analyses, identifying their therapeutic potential against <i>S. aureus</i>-induced mastitis. The bacteriophages were identified as members of the <i>Herelleviridae</i> family, exhibiting stability across broad pH (2-12) and temperature (37-70°C) ranges, as well as strong antibacterial activity at low multiplicity of infection (MOI) levels. Genomic analysis revealed that the conservation of lysis-related genes (holin and endolysin) is responsible for their lytic capabilities. Additionally, protein structural predictions revealed multi-domain structures in their endolysins, enhancing their lytic potential. These findings suggest that OPT-SA02, OPT-SC01, and OPT-SX11 show significant promise as alternative treatments for bovine mastitis.IMPORTANCEBovine mastitis, caused by pathogens such as <i>Staphylococcus aureus</i> and <i>Staphylococcus xylosus</i>, remains a major challenge in dairy farming, leading to significant economic losses and reduced milk quality. The increasing prevalence of antibiotic-resistant strains further complicates treatment, emphasizing the need for alternative strategies. This study identifies three newly isolated bacteriophages with effective antibacterial activity against these pathogens and provides comprehensive genomic and structural insights into their mechanisms. Genomic characterization revealed conserved lytic cassettes and genetic diversity within related bacteriophages, offering a deeper understanding of their evolutionary relationships and potential applications. Furthermore, protein structure analysis of the endolysin derived from these bacteriophages identified multi-domain architectures with preserved catalytic cores, underscoring their lytic efficacy against bacterial cell walls. These findings advance the understanding of the genetic and structural mechanisms of bacteriophage-mediated lysis and highlight their potential as sustainable tools for managing bovine mastitis and improving milk quality in dairy farming.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0190124"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural basis of receptor-binding adaptation of human-infecting H3N8 influenza A virus.","authors":"Tianjiao Hao, Yufeng Xie, Yan Chai, Wei Zhang, Di Zhang, Jianxun Qi, Yi Shi, Hao Song, George F Gao","doi":"10.1128/jvi.01065-24","DOIUrl":"10.1128/jvi.01065-24","url":null,"abstract":"<p><p>Recent avian-origin H3N8 influenza A virus (IAV) that have infected humans pose a potential public health concern. Alterations in the viral surface glycoprotein, hemagglutinin (HA), are typically required for IAVs to cross the species barrier for adaptation to a new host, but whether H3N8 has adapted to infect humans remains elusive. The observation of a degenerative codon in position 228 of HA in human H3N8 A/Henan/4-10/2022 protein sequence, which could be residue G or S, suggests a dynamic viral adaptation for human infection. Previously, we found this human-isolated virus has shown the ability to transmit between ferrets via respiratory droplets, with the HA-G228S substitution mutation emerging as a critical determinant for the airborne transmission of the virus in ferrets. Here, we investigated the receptor-binding properties of these two H3N8 HAs. Our results showed H3N8 HAs have dual receptor-binding properties with a preference for avian receptor binding, and G228S slightly increased binding to human receptors. Cryo-electron microscopy structures of the two H3N8 HAs with avian and human receptor analogs revealed the basis for dual receptor binding. Mutagenesis studies reveal that the Q226L mutation shifts H3N8 HA's receptor preference from avian to human, while the G228S substitution enhances binding to both receptor types. H3N8 exhibits distinct antigenic sites compared to H3N2, prompting concerns regarding vaccine efficacy. These findings suggest that the current H3N8 human isolates are yet to adapt for efficient human-to-human transmission and further continuous surveillance should be implemented.IMPORTANCEInfluenza virus transmission remains a public health concern currently. H3N8 subtype influenza A viruses infect humans and their HAs acquire the ability to bind to both human and avian receptors, posing a threat to human health. We have solved and analyzed the structural basis of dual receptor binding of recently human-infecting H3N8 HA, and we demonstrate that the G228S enhances human receptor binding and adaptation. We also found that HN/4-10 H3N8 HA has distinct antigenic sites, which challenges vaccine efficacy. Taken together, our work is critical to the prevention and control of human H3 influenza virus infection.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0106524"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915789/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483575","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":"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.00023-25","DOIUrl":"10.1128/jvi.00023-25","url":null,"abstract":"<p><p>A successful strategy employed by RNA viruses to achieve replication is to evade host cell RNase degradation. However, the mechanisms through which plus-strand RNA viruses effectively shield viral RNA from cellular ribonuclease degradation remain unclear. In this study, we identified the phenomenon whereby plus-strand RNA viruses, including avian leukosis virus subgroup J (ALV-J), reticuloendotheliosis virus (REV), chicken astrovirus (CAstV), and porcine epidemic diarrhea virus (PEDV), hijacked host cellular Musashi homolog 1 (MSI1). These viruses upregulated MSI1 expression and facilitated its translocation from the cytoplasmic periphery to a position proximal to and within the nucleus, thereby protecting viral RNA from degradation. Mechanistic analyses revealed that these viruses use distinct regions, the unique (U3) region or three prime untranslated region (3'UTR), to engage with MSI1, consequently shielding their viral RNA from cytoplasmic ribonuclease degradation. These results offer significant implications for understanding the replication tactics used by plus-strand RNA viruses, thereby advancing our understanding of their biological behaviors.IMPORTANCEThe intricate interplay between RNA viruses and host cell RNA regulation encompasses viral mechanisms designed to circumvent RNase-mediated degradation. However, the specific strategies employed by plus-strand RNA viruses to shield their RNA from host ribonucleases remain inadequately characterized. In this study, Musashi homolog 1 (MSI1) is predominantly localized in the cytoplasm of normal cells, distinct from the nucleus. Following infection by plus-strand RNA viruses such as avian leukosis virus subgroup J (ALV-J), reticuloendotheliosis virus (REV), chicken astrovirus (CAstV), and porcine epidemic diarrhea virus (PEDV), these viruses hijack MSI1 to relocate near and within the nucleus. This hijacking is facilitated by specific regions, including unique or three prime untranslated regions, thereby preventing viral RNA from degradation by cytoplasmic ribonucleases. These findings have significant implications for elucidating the replication strategies of plus-strand RNA viruses, thereby advancing our understanding of their biological mechanisms.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0002325"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399545","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}