Journal of Virology最新文献

{"title":"Correction for Liang et al., \"Chicken or Porcine Aminopeptidase N Mediates Cellular Entry of Pseudoviruses Carrying Spike Glycoprotein from the Avian Deltacoronaviruses HKU11, HKU13, and HKU17\".","authors":"Qi-Zhang Liang, Bin Wang, Chun-Miao Ji, Feifan Hu, Pan Qin, Yaoyu Feng, Yan-Dong Tang, Yao-Wei Huang","doi":"10.1128/jvi.01631-24","DOIUrl":"https://doi.org/10.1128/jvi.01631-24","url":null,"abstract":"","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583780","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":"Cellular NONO protein binds to the flavivirus replication complex and promotes positive-strand RNA synthesis.","authors":"Honggen Yuan, Yun Luo, Jiahui Zou, Junmei Zhang, Jinhua Zhang, Gang Cao, Shengbo Cao, Huanchun Chen, Yunfeng Song","doi":"10.1128/jvi.00297-24","DOIUrl":"https://doi.org/10.1128/jvi.00297-24","url":null,"abstract":"<p><p>A cellular protein, non-POU-domain-containing octamer binding protein (NONO), bound to the replication complex of Japanese encephalitis virus (JEV) by directly interacting with the viral 3' UTR RNA and NS3 protein. These interactions were also identified in West Nile virus (WNV) and Zika virus (ZIKV). The infection of JEV or the expression of JEV NS3 protein in cells could induce relocation of NONO protein from the nucleus to the cytoplasm. In JEV-infected cells, the NS3, NS5, and viral RNA could be concurrently detected in the immunoprecipitation by the NONO-specific antibody, suggesting that NONO could integrate into the replication complex of JEV. Further results of co-immunoprecipitation assays showed that NONO protein interacted with NS3 helicase domains 1 and 2 by its two RNA recognize motifs (RRMs). The knockdown and knockout of NONO in cells could significantly reduce the replication of JEV and ZIKV but had no effect on the replication of vesicular stomatitis virus (VSV). The effect of NONO protein on JEV proliferation occurred during the replication stage, rather than the attachment and entry stages. The level of viral positive-strand RNA in NONO knockout cells was significantly reduced than that in wild-type cells at 12-48 h post-JEV infection. However, the level of negative-strand virus RNA had no difference between NONO knockout and wild-type cells at 12-24 h post-infection. In summary, our study identified a cellular protein that bound to the replication complex of flavivirus and facilitated the synthesis of positive-strand RNA.IMPORTANCEOver half of the world's population is at risk of flaviviruses infection, posing a serious global health concern. To date, there are no antiviral drugs or treatments for the severe symptoms caused by the infection of flaviviruses. Some cellular proteins could participate in the replication of virus, and these cellular proteins were also ideal targets in antiviral strategy. Here, we identified cellular NONO protein was recruited by flavivirus NS3 protein to the cytoplasm, serving as a \"scaffold\" for viral replication complex. Our findings also revealed that NONO protein was critical for flavivirus positive-strand RNA synthesis. Specific areas where NONO interacted with flavivirus NS3 proteins and viral UTRs have also been identified. These results propose a new mechanism for cellular protein to participate in flavivirus replication and also raise a new potential anti-flavivirus strategy.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583778","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 wild-type vaccine doses on BA.5 hybrid immunity, disease severity, and XBB reinfection risk.","authors":"Daxiang Chen, Weihong Zhang, Bin Xiao, Banglao Xu, Xiaoyun Yang, Shidong Deng, Guichang Li, Gang Yang, Jinpeng Cao, Xinyue Mei, Qi Luo, Peiyu Huang, Xi Sun, Jie Su, Nanshan Zhong, Zhuxiang Zhao, Zhongfang Wang","doi":"10.1128/jvi.01285-24","DOIUrl":"https://doi.org/10.1128/jvi.01285-24","url":null,"abstract":"<p><p>Vaccination against the wild-type (WT) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus did not produce detectable levels of neutralizing antibodies (NAbs) against the BA.5 strain before it emerged. However, coronavirus disease-2019 (COVID-19) severity varied highly between unvaccinated, partially vaccinated, and fully vaccinated individuals, for unknown reasons. We assessed the severity of BA.5 infection and the risk of XBB strain reinfection and measured serum levels of NAbs against WT, BA.5, and XBB.1.9.1 SARS-CoV-2 strains at varying time points in 1,373 individuals who received zero, one, two, or three WT vaccine doses. We found that two to three WT doses significantly increased WT and BA.5 NAb levels and reduced the incidence of COVID-19-associated pneumonia upon BA.5 strain infection compared to zero to one dose. Regarding XBB reinfection, those who received two to three doses and were infected with the BA.5 variant exhibited a significantly lower reinfection risk compared to those who received zero to one dose. RNA analysis revealed that the differentially expressed genes between the two to three dose and unvaccinated groups were enriched in B cell activation, cytokine-cytokine receptor interaction, complement, and monocyte activation functions-indicating that vaccination increased the antibody response and reduced inflammation. Our results suggest that multiple antigen exposures to either matched or unmatched SARS-COV-2 variants, through vaccination or infection, may be necessary to achieve significant immune imprinting.IMPORTANCEThe administration of coronavirus disease-2019 (COVID-19) vaccines that do not perfectly match the viral strains that individuals become infected with has been found to impact the resultant illness severity-although the precise mechanism underlying this phenomenon remains unclear. We assessed viral clearance, as well as serum levels of inflammatory cytokines and neutralizing antibodies (NAbs) against wild-type, BA.5, and XBB.1.9.1 variants of the severe acute respiratory syndrome coronavirus 2 among individuals who received varying doses of such strain-mismatched vaccines. Notably, vaccination with ≥2 doses of strain-mismatched COVID-19 vaccines appeared to stimulate the production of specific NAbs during infection with new variants, as well as attenuate the inflammatory response and enhance viral clearance. Such vaccination regimens can also reduce the risk of reinfection. These findings may be important for guiding the development of future COVID-19 vaccination strategies that target both matched and mismatched viral variants.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583781","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":"Neuroinvasive virus utilizes a lipid droplet surface protein, perilipin2, to restrict apoptosis by decreasing Bcl-2 ubiquitination.","authors":"Qianruo Wang, Jianqing Zhao, Mai Zhang, Meixin Sun, Zhen F Fu, Ling Zhao, Ming Zhou","doi":"10.1128/jvi.01607-24","DOIUrl":"https://doi.org/10.1128/jvi.01607-24","url":null,"abstract":"<p><p>Lipid droplets (LDs) can interact with other organelles to regulate cell death, and it has also been reported to play an important role in virus replication. However, the interplay among LDs, cell death, and viral replication remains unclear. Neuroinvasive viruses, such as Japanese encephalitis virus (JEV), rabies virus (RABV), and encephalomyocarditis virus (EMCV) still threaten global public health and raise intensive concerns. Here, we reveal that neuroinvasive virus infection enhances cellular triglyceride biosynthesis by upregulating the expression of diacylglycerol O-acyltransferase 2 (DGAT2) to promote LD formation and increase the expression of Perilipin 2 (PLIN2), an LD surface protein, which consequently facilitates neuroinvasive virus replication. Furthermore, PLIN2 could reduce mitochondrial damage and suppress apoptosis by restoring mitochondrial potential and interacting with anti-apoptotic protein Bcl-2, specifically the 136-209 amino acid region, to interrupt the BAX-Cytc-caspase-3 apoptotic pathway by decreasing the K48-linked ubiquitination of Bcl-2 at the 17th lysine. Together, we elucidate that neuroinvasive virus utilizes an LD surface protein to restrict the apoptosis of infected cells, providing a fresh insight into the pathogenesis and antiviral therapeutics development of neuroinvasive viruses.</p><p><strong>Importance: </strong>The neuroinvasive virus is a kind of pathogen that is capable of infiltrating and infecting the central nervous system to potentially induce severe neurological damage and disorders, which pose a significant threat to public health. Here, we found that neuroinvasive viruses can utilize an LD surface protein PLIN2 to facilitate viral replication. Notably, PLIN2 could reduce mitochondrial damage and suppress apoptosis by restoring mitochondrial potential and interacting with anti-apoptotic protein Bcl-2, specifically the 136-209 amino acid region, to interrupt the BAX-Cytc-caspase-3 apoptotic pathway by decreasing the K48-linked ubiquitination of Bcl-2 at the 17th lysine. This study reveals a common strategy for neuroinvasive viruses to avoid apoptosis of infected cells by employing LDs, which extends the important role of LDs in viral pathogenesis and may inspire further research in this field.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583785","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":"Age-specific dynamics of neutralizing antibodies, cytokines, and chemokines in response to La Crosse virus infection in mice.","authors":"Reem Alatrash, Varun Vaidya, Bobby Brooke Herrera","doi":"10.1128/jvi.01762-24","DOIUrl":"https://doi.org/10.1128/jvi.01762-24","url":null,"abstract":"<p><p>La Crosse virus (LACV) is a primary cause of pediatric arboviral encephalitis in the United States, particularly affecting children aged 16 years or younger. This age-related susceptibility extends to murine models, where weanling mice (3 weeks old) succumb to LACV infection, while adults (≥6 weeks old) demonstrate resistance. Despite its clinical relevance, the host immune response to LACV is not fully understood. In this study, we investigated the roles of neutralizing antibodies (nAbs), cytokines, and chemokines in weanling and adult mice following infection with 5 × 10⁵ plaque-forming units (PFU) of LACV. Weanling mice demonstrated early disease onset with elevated peripheral viremia, but passive transfer of adult serum, confirmed to have nAbs, to naïve weanlings prior to infection completely rescued them from death. Moreover, adult mice had increased Th1 cytokines, Th9/Th17/Th22/Treg cytokines, and many chemokines. In contrast, weanlings had higher Th2 cytokines, correlating with symptoms onset. Flow cytometry and intracellular cytokine staining further demonstrated that weanling mice produced higher levels of IL-4 by CD4⁺ and CD8⁺ T cells compared to adults, regardless of infection status. Conversely, LACV-infected adult mice had increased IFN-γ production by CD8⁺ T cells compared to uninfected controls. Finally, the adoptive transfer of splenocytes from immune adult mice to naïve weanlings delayed neurological symptoms and improved survival. In conclusion, this study links nAbs and cytokine and chemokine responses to protective immunity in adult mice, contrasting with the pathogenesis seen in weanlings. These findings underscore the importance of further research into innate and adaptive immune mechanisms during LACV infection.IMPORTANCELa Crosse virus (LACV) is a primary cause of pediatric encephalitis in the United States, with an impact on children aged 16 years or younger. This age-related susceptibility is recapitulated in mouse models, where young mice succumb to LACV-induced disease, while adults demonstrate resistance. Our understanding of host responses to LACV remains underexplored. This study sheds light on the dynamics of neutralizing antibodies (nAbs), cytokines, and chemokines following LACV infection in both adult and weanling mice. Our study reveals age-specific variations in viremia, neutralizing antibody titers, survivability, and levels of cytokines and chemokines. Adult mice exhibit significantly elevated levels of Th1 cytokines, contrasting with elevated levels of Th2 cytokines observed in weanling mice, often coinciding with the onset of symptoms. These data reveal age-specific dynamics in cytokines and chemokines associated with protective versus pathogenic immunity, emphasizing the need for further studies on innate and adaptive immunity.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583776","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":"Lethal model for respiratory syncytial virus infection using C57BL/6 mice.","authors":"Tatsuki Takahashi, Sodbayasgalan Amarbayasgalan, Shiori Ueno, Yoshiro Sugiura, Enkhjin Dorjsuren, Kenta Shimizu, Wataru Kamitani","doi":"10.1128/jvi.01772-24","DOIUrl":"https://doi.org/10.1128/jvi.01772-24","url":null,"abstract":"<p><p>Respiratory syncytial virus (RSV) infection is a major infectious disease affecting public health. Infants and elderly infected with RSV can develop severe respiratory symptoms. A mouse model mimicking human RSV infection could be useful in elucidating the pathogenesis of RSV. However, previous mouse models did not adequately mimic the pathophysiology of human patients. We attempted to establish a new mouse-adapted RSV strain via serial passaging of mice. We rescued the MP11 virus (which had one non-synonymous substitution in each of the F, G, and L genes) through serial passaging in mice. The MP11 virus was inoculated into mice to evaluate whether it had adapted to the mouse. Viral RNA levels in the lungs of 25-week-old mice infected with MP11 virus were higher than those in the lungs of mice infected with A2 virus. There was a high infiltration of inflammatory cells and high expression of several inflammatory cytokines (IFN-γ, CCL2, TNF-α, and IL-6) in the MP11 virus-infected lungs. Furthermore, the MP11 virus can also cause lethal pneumonia in mice via high-concentration inoculation. These results indicated that the MP11 virus is a more mouse-adapted strain than the A2 virus. We generated a recombinant MP11 virus (rMP11) using reverse genetics. The rMP11 virus could grow in the lungs of mice, similar to the parent MP11 virus. In conclusion, we successfully established a new mouse-adapted strain, MP11, and reverse genetics for this strain. These MP11 and rMP11 viruses could contribute to mouse experiments aimed at elucidating RSV pathogenesis.</p><p><strong>Importance: </strong>A mouse model of respiratory syncytial virus (RSV) infection is useful for fundamental research aimed at developing antiviral drugs. Previous mouse models of RSV infection were unable to adequately mimic the pathophysiology of human patients due to the low amplification efficiency of this virus in the mouse lung. Furthermore, mice other than BALB/C mice are difficult to use for the RSV infectious model. We established a new mouse-adapted RSV strain, MP11. The MP11 virus can cause severe pneumonia in C57BL/6 mice and efficiently replicate and induce inflammation in the lung. Therefore, C57BL/6 mice can be used for RSV infection experiments using MP11 virus. We established a reverse genetics system for the MP11 virus using our mouse model. This system enables detailed analyses of the MP11 virus, such as functional analysis of each viral protein. Our study provides techniques that can advance fundamental research in elucidating the pathogenesis of RSV infections.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583784","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":"Studying bats using a One Health lens: bridging the gap between bat virology and disease ecology.","authors":"Victoria Gonzalez, Arianna M Hurtado-Monzón, Sabrina O'Krafka, Elke Mühlberger, Michael Letko, Hannah K Frank, Eric D Laing, Kendra L Phelps, Daniel J Becker, Vincent J Munster, Darryl Falzarano, Tony Schountz, Stephanie N Seifert, Arinjay Banerjee","doi":"10.1128/jvi.01453-24","DOIUrl":"https://doi.org/10.1128/jvi.01453-24","url":null,"abstract":"<p><p>Accumulating data suggest that some bat species host emerging viruses that are highly pathogenic in humans and agricultural animals. Laboratory-based studies have highlighted important adaptations in bat immune systems that allow them to better tolerate viral infections compared to humans. Simultaneously, ecological studies have discovered critical extrinsic factors, such as nutritional stress, that correlate with virus shedding in wild-caught bats. Despite some progress in independently understanding the role of bats as reservoirs of emerging viruses, there remains a significant gap in the molecular understanding of factors that drive virus spillover from bats. Driven by a collective goal of bridging the gap between the fields of bat virology, immunology, and disease ecology, we hosted a satellite symposium at the 2024 American Society for Virology meeting. Bringing together virologists, immunologists, and disease ecologists, we discussed the intrinsic and extrinsic factors such as virus receptor engagement, adaptive immunity, and virus ecology that influence spillover from bat hosts. This article summarizes the topics discussed during the symposium and emphasizes the need for interdisciplinary collaborations and resource sharing.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583787","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 temperature-sensitive and less immunogenic Sendai virus for efficient gene editing.","authors":"Christian S Stevens, Jillian C Carmichael, Ruth Watkinson, Shreyas Kowdle, Rebecca A Reis, Kory Hamane, Jason Jang, Arnold Park, Olivier Pernet, Wannisa Khamaikawin, Patrick Hong, Patricia Thibault, Aditya Gowlikar, Dong Sung An, Benhur Lee","doi":"10.1128/jvi.00832-24","DOIUrl":"https://doi.org/10.1128/jvi.00832-24","url":null,"abstract":"<p><p>The therapeutic potential of gene editing technologies hinges on the development of safe and effective delivery methods. In this study, we developed a temperature-sensitive and less immunogenic Sendai virus (ts SeV) as a novel delivery vector for CRISPR-Cas9 and for efficient gene editing in sensitive human cell types with limited induction of an innate immune response. ts SeV demonstrates high transduction efficiency in human CD34⁺ hematopoietic stem and progenitor cells (HSPCs) including transduction of the CD34⁺/CD38^-/CD45RA^-/CD90⁺(Thy1⁺)/CD49f^high stem cell enriched subpopulation. The frequency of <i>CCR5</i> editing exceeded 90% and bi-allelic <i>CCR5</i> editing exceeded 70% resulting in significant inhibition of HIV-1 infection in primary human CD14⁺ monocytes. These results demonstrate the potential of the ts SeV platform as a safe, efficient, and flexible addition to the current gene-editing tool delivery methods, which may help further expand the possibilities in personalized medicine and the treatment of genetic disorders.</p><p><strong>Importance: </strong>Gene editing has the potential to be a powerful tool for the treatment of human diseases including HIV, β-thalassemias, and sickle cell disease. Recent advances have begun to overcome one of the major limiting factors of this technology, namely delivery of the CRISPR-Cas9 gene editing machinery, by utilizing viral vectors. However, gene editing therapies have yet to be implemented due to inherent risks associated with the DNA viral vectors typically used for delivery. As an alternative strategy, we have developed an RNA-based Sendai virus CRISPR-Cas9 delivery vector that does not integrate into the genome, is temperature sensitive, and does not induce a significant host interferon response. This recombinant SeV successfully delivered CRISPR-Cas9 in primary human CD14+ monocytes <i>ex vivo</i> resulting in a high level of CCR5 editing and inhibition of HIV infection.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569049","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 human monoclonal antibody neutralizing SARS-CoV-2 Omicron variants containing the L452R mutation.","authors":"Saskia C Stein, Guido Hansen, George Ssebyatika, Luisa J Ströh, Okechukwu Ochulor, Elisabeth Herold, Britta Schwarzloh, Doris Mutschall, Jasmin Zischke, Anne K Cordes, Talia Schneider, Imke Hinrichs, Rainer Blasczyk, Hannah Kleine-Weber, Markus Hoffmann, Florian Klein, Franziska K Kaiser, Mariana Gonzalez-Hernandez, Federico Armando, Malgorzata Ciurkiewicz, Georg Beythien, Stefan Pöhlmann, Wolfgang Baumgärtner, Albert Osterhaus, Thomas F Schulz, Thomas Krey","doi":"10.1128/jvi.01223-24","DOIUrl":"https://doi.org/10.1128/jvi.01223-24","url":null,"abstract":"<p><p>The effectiveness of SARS-CoV-2 therapeutic antibodies targeting the spike (S) receptor-binding domain (RBD) has been hampered by the emergence of variants of concern (VOCs), which have acquired mutations to escape neutralizing antibodies (nAbs). These mutations are not evenly distributed on the RBD surface but cluster on several distinct surfaces, suggesting an influence of the targeted epitope on the capacity to neutralize a broad range of VOCs. Here, we identified a potent nAb from convalescent patients targeting the receptor-binding domain of a broad range of SARS-CoV-2 VOCs. Except for the Lambda and BA.2.86 variants, this nAb efficiently inhibited the entry of most tested VOCs, including Omicron subvariants BA.1, BA.2, XBB.1.5, and EG.5.1 and to a limited extent also BA.4/5, BA.4.6, and BQ.1.1. It bound recombinant S protein with picomolar affinity, reduced the viral load in the lung of infected hamsters, and prevented the severe lung pathology typical for SARS-CoV-2 infections. An X-ray structure of the nAb-RBD complex revealed an epitope that does not fall into any of the conventional classes and provided insights into its broad neutralization properties. Our findings highlight a conserved epitope within the SARS-CoV-2 RBD that should be preferably targeted by therapeutic antibodies and inform rational vaccine development.IMPORTANCETherapeutic antibodies are effective in preventing severe disease from SARS-CoV-2 infection and constitute an important option in pandemic preparedness, but mutations within the S protein of virus variants (e.g., a mutation of L452) confer resistance to many of such antibodies. Here, we identify a human antibody targeting the S protein receptor-binding domain (RBD) with an elevated escape barrier and characterize its interaction with the RBD functionally and structurally at the atomic level. A direct comparison with reported antibodies targeting the same epitope illustrates important differences in the interface, providing insights into the breadth of antibody binding. These findings highlight the relevance of an extended neutralization profiling in combination with biochemical and structural characterization of the antibody-RBD interaction for the selection of future therapeutic antibodies, which may accelerate the control of potential future pandemics.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569048","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":"FoxK1 and FoxK2 cooperate with ORF45 to promote late lytic replication of Kaposi's sarcoma-associated herpesvirus.","authors":"Qingyang Chen, Xiaojuan Li, Li Quan, Rihong Zhou, Xiangpeng Liu, Lu Cheng, Ronit Sarid, Ersheng Kuang","doi":"10.1128/jvi.00779-24","DOIUrl":"https://doi.org/10.1128/jvi.00779-24","url":null,"abstract":"<p><p>Lytic replication is essential for persistent infection of Kaposi's sarcoma-associated herpesvirus (KSHV) and the pathogenesis of related diseases, and many cellular pathways are hijacked by KSHV proteins to initiate and control the lytic replication of this virus. However, the mechanism involved in KSHV lytic replication from the early to the late phases remains largely undetermined. We previously revealed that KSHV open reading frame 45 (ORF45) plays important roles in late transcription and translation. In the present study, we revealed that the Forkhead box proteins FoxK1 and FoxK2 are ORF45-binding proteins and are essential for KSHV lytic gene expression and virion production, and that depletion of FoxK1 or FoxK2 significantly suppresses the expression of many late viral genes. FoxK1 and FoxK2 directly bind to the promoters of several late viral genes, ORF45 augments the promoter binding and transcriptional activity of FoxK1 and FoxK2, and then FoxK1 or FoxK2 cooperates with ORF45 to promote late viral gene expression. Our findings suggest that ORF45 interacts with FoxK1 and FoxK2 and promotes their occupancy on a cluster of late viral promoters and their subsequent transcriptional activity; consequently, FoxK1 and FoxK2 promote late viral gene expression to facilitate KSHV lytic replication.IMPORTANCEThe forkhead box proteins FoxK1 and FoxK2 can act as transcriptional inhibitors or activators to regulate several important processes, including aerobic glycolysis, metabolism, autophagy, and antiviral responses. However, the subversion and functions of FoxK1 and FoxK2 during KSHV infection and the pathogenesis of related diseases remain unknown. Here, we revealed that ORF45 binds to FoxK1 and FoxK2 and increases their transcriptional activity during KSHV lytic replication; consequently, FoxK1 and FoxK2 bind to late viral promoters and cooperate with ORF45 to promote late lytic gene expression. Our findings reveal two new ORF45 partners and a new function of ORF45 in which it utilizes FoxK1 and FoxK2 to promote transcription during late KSHV lytic replication.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569068","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}