Journal of Virology最新文献

{"title":"Structural analysis of a non-pathogenic hare calicivirus capsid bound to a histo-blood group antigen co-factor.","authors":"Grant S Hansman, Todd Reese, Marie Pancera, Penny A Rudd, Veronika Masic, Thomas Haselhorst, Mark von Itzstein","doi":"10.1128/jvi.01675-24","DOIUrl":"10.1128/jvi.01675-24","url":null,"abstract":"","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0167524"},"PeriodicalIF":4.0,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11651000/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603490","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":"Both chebulagic acid and punicalagin inhibit respiratory syncytial virus entry via multi-targeting glycoprotein and fusion protein.","authors":"Yingcai Xiong, Keyu Tao, Tao Li, Yinghui Zhou, Zhaowei Zhang, Weiying Ou, Zhao Wang, Shouchuan Wang, Yayi Hou, Peng Cao, Jianjian Ji","doi":"10.1128/jvi.01536-24","DOIUrl":"10.1128/jvi.01536-24","url":null,"abstract":"<p><p>Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections, with no currently available small-molecule drugs that are both safe and effective. A major obstacle in antiviral drug development is the rapid emergence of drug-resistant viral strains. Targeting multiple viral compounds may help mitigate the development of resistance. Herein, we conducted a drug screening using the Antiviral Traditional Chinese Medicine Active Compound Library, aiming to identify compounds that simultaneously target the RSV fusion (F) protein, glycoprotein (G), and the host heparan sulfate proteoglycans (HSPGs). From this screening, 10 candidate compounds were identified for their ability to interact with all three targets. Among these 10 candidates, chebulagic acid (CHLA) and punicalagin (PUG) demonstrated the most potent inhibition of RSV replication. <i>In vitro</i> dose-response assays confirmed the antiviral efficacy of CHLA (IC50: 0.07864 µM) and PUG (IC50: 0.08065 µM). Further experiments revealed both CHLA and PUG disrupt RSV attachment and membrane fusion by targeting the RSV-F and G proteins, rather than HSPG. Notably, CHLA and PUG were found to bind to the CX3C motif of the RSV-G protein, with docking assays predicting their binding sites at cysteines 176 and 182. Additionally, CHLA enhanced the conformational stability of the RSV-F protein before fusion. In an <i>in vivo</i> study, both CHLA and PUG were shown to alleviate RSV-induced pulmonary pathology by reducing viral titers, mitigating lung injury, and suppressing the inflammatory responses in the lungs. Our findings suggest that CHLA and PUG hold potential as therapeutic agents for RSV infection.IMPORTANCEA significant challenge in developing anti-respiratory syncytial virus (RSV) agents is the rapid emergence of resistant viral strains. Designing drugs that target multiple viral components can effectively reduce the likelihood of developing resistant strains. In this study, we screened compounds from the Antiviral Traditional Chinese Medicine Active Compound Library, aiming to simultaneously targe the RSV fusion (F) protein, glycoprotein (G), and host heparan sulfate proteoglycans (HSPGs). Our findings revealed that chebulagic acid (CHLA) and punicalagin (PUG) significantly inhibited RSV replication both <i>in vitro</i> and <i>in vivo</i> and interacted with all three targets. Both CHLA and PUG were able to disrupt RSV attachment and membrane fusion. Mechanistically, CHLA and PUG were found to bind to the CX3C motif of the RSV-G protein, with CHLA also enhancing the conformational stability of the RSV-F protein before fusion. In conclusion, our study suggests that CHLA and PUG hold promise as therapeutic agents against RSV infection.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0153624"},"PeriodicalIF":4.0,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11650974/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142605692","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":"Effects of immunoproteasome inhibition on acute respiratory infection with murine hepatitis virus strain 1.","authors":"Jacob C Steigmann, Xiaofeng Zhou, Lauren N Suttenberg, Irha Salman, Zainab F Rehmathullah, Jason B Weinberg","doi":"10.1128/jvi.01238-24","DOIUrl":"10.1128/jvi.01238-24","url":null,"abstract":"<p><p>The immunoproteasome (IP) is a predominantly inducible component of the ubiquitin proteasome system that plays key roles in multiple aspects of immune function, inflammation, and protein homeostasis. We used murine hepatitis virus strain 1 (MHV-1), a mouse coronavirus, to define the role of IP activity during acute coronavirus respiratory infection. Expression of the β5i subunit of the IP and cytokines that induce IP activity, including IFN-γ, TNF-α, and IFN-β, increased in lungs and livers of CH3/HeJ mice following intranasal infection with MHV-1. IP inhibition using ONX-0914 did not affect MHV-1 replication in bone marrow-derived dendritic cells <i>in vitro</i>. IP inhibition <i>in vivo</i> exacerbated virus-induced weight loss and mortality but had no effect on virus replication in lungs or livers. IP inhibition had minimal effect on virus-induced pulmonary inflammation but led to substantially increased liver pathology, including greater upregulation of pro-inflammatory cytokines and histological evidence of inflammation and necrosis. Those findings were associated with evidence of increased endoplasmic reticulum stress although not with accumulation of ubiquitinated protein. Our results indicate that the IP is a protective host factor during acute MHV-1 infection.</p><p><strong>Importance: </strong>Inflammatory responses triggered by acute infection by respiratory viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) drive morbidity and mortality. Infection of mice with murine hepatitis virus strain 1 (MHV-1), a mouse coronavirus, is a useful model to study the pathogenesis of coronavirus respiratory infections. The immunoproteasome is an inducible component of the ubiquitin proteasome system that is poised to contribute to multiple aspects of immune function, inflammation, and protein homeostasis during an infection. We used the MHV-1 model to define the role of the immunoproteasome in coronavirus pathogenesis. We found that immunoproteasome subunit expression increases in the lungs and the liver during acute MHV-1 respiratory infection. Inhibition of immunoproteasome activity did not affect MHV-1 replication but increased MHV-1-induced weight loss, mortality, and inflammation in lungs and livers. Thus, our findings indicate that the immunoproteasome is a critical protective host factor during coronavirus respiratory infection.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0123824"},"PeriodicalIF":4.0,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11650983/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142605694","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":"Dissecting the role of the HA1-226 leucine residue in the fitness and airborne transmission of an A(H9N2) avian influenza virus.","authors":"Xiangjie Sun, Jessica A Belser, Joanna A Pulit-Penaloza, Nicole Brock, Troy J Kieran, Claudia Pappas, Hui Zeng, Terrence M Tumpey, Taronna R Maines","doi":"10.1128/jvi.00928-24","DOIUrl":"10.1128/jvi.00928-24","url":null,"abstract":"<p><p>A better understanding of viral factors that contribute to influenza A virus (IAV) airborne transmission is crucial for pandemic preparedness. A limited capacity for airborne transmission was recently observed in a human A(H9N2) virus isolate (A/Anhui-Lujiang/39/2018, AL/39) that possesses a leucine (L) residue at position HA1-226 (H3 numbering), indicative of human-like receptor binding potential. To evaluate the roles of the residue at this position in virus fitness and airborne transmission, a wild-type AL/39 (AL/39-wt) and a mutant virus (AL/39-HA1-L226Q) with a single substitution at position HA1-226 from leucine to glutamine (Q), a consensus residue in avian influenza viruses, were rescued and assessed in the ferret model. The AL/39-HA1-L226Q virus lost the ability to transmit by air, although the virus had a comparable capacity for replication, induced similar levels of host innate immune responses, and was detected at comparable levels in the air surrounding the inoculated ferrets relative to AL/39-wt virus. However, ferrets showed a lower susceptibility to AL/39-HA1-L226Q virus infection compared to the AL/39-wt virus. Furthermore, the AL/39-wt and AL/39-HA1-L226Q viruses each gained dominance in different anatomic sites in the respiratory tract in a co-infection competition model in ferrets. Taken together, our findings demonstrate that the increasing dominance of HA1-L226 residue in an avian A(H9N2) virus plays multifaceted roles in virus infection and transmission in the ferret model, including improved virus fitness and infectivity.</p><p><strong>Importance: </strong>Although the capacity for human-like receptor binding is a key prerequisite for non-human origin influenza A virus (IAV) to become airborne transmissible in mammalian hosts, the underlying molecular basis is not well understood. In this study, we investigated a naturally occurring substitution (leucine to glutamine) at residue 226 in the HA of an avian-origin A(H9N2) virus and assessed the impact on virus replication and airborne transmission in the ferret model. We demonstrate that the enhanced airborne transmission associated with the HA1-L226 virus was mainly due to the increased infectivity of the virus. Interestingly, we found that, unlike most sites in the ferret respiratory tract, ferret ethmoid turbinate lined with olfactory epithelium favors replication of the AL/39-HA1-L226Q virus, suggesting that this site may serve as a unique niche for IAV with avian-like receptor binding specificity to potentially allow the virus to spread to extrapulmonary tissues and to facilitate adaptation of the virus to human hosts.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0092824"},"PeriodicalIF":4.0,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11651004/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569052","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":"E2F3-dependent activation of FAM111B restricts mouse cytomegalovirus replication in primate cells.","authors":"Eleonore Ostermann, Laura-Marie Luoto, Michaela Clausen, Sanamjeet Virdi, Wolfram Brune","doi":"10.1128/jvi.01349-24","DOIUrl":"10.1128/jvi.01349-24","url":null,"abstract":"<p><p>Cytomegaloviruses are highly species-specific as they replicate only in cells of their own or a closely related species. For instance, human cytomegalovirus cannot replicate in rodent cells, and mouse cytomegalovirus (MCMV) cannot replicate in human and monkey cells. However, the mechanisms underlying the host species restriction remain poorly understood. We have previously shown that passaging MCMV in human retinal pigment epithelial cells allows the virus to replicate to high titers in these cells due to the accumulation of adaptive mutations, such as loss-of-function mutations in the viral M117 gene. The M117 protein interacts with E2F transcription factors and activates E2F-dependent transcription. Here, we show that activation of E2F3 is primarily responsible for MCMV's inability to replicate in human cells. By transcriptome analysis, we identified two E2F3-induced serine proteases, FAM111A and FAM111B, as potential host restriction factors. By using shRNA-mediated gene knockdown and CRISPR/Cas9-mediated gene knockout, we demonstrated that FAM111B, but not its paralog FAM111A, suppresses MCMV replication in human and rhesus macaque cells. By immunofluorescence, we detected FAM111B predominantly in the nucleus of infected cells with enrichment in viral replication compartments, suggesting that it might play a role during viral replication. The fact that the FAM111B gene is conserved in primates but absent in rodents suggests that MCMV has not evolved to evade or counteract this restriction factor, which is not present in its natural host.</p><p><strong>Importance: </strong>Viruses must counteract host cell defenses to facilitate viral replication. Viruses with a narrow host range, such as the cytomegaloviruses, are unable to counteract cellular defenses in cells of a foreign species. However, little is known about the cellular host range factors restricting cytomegalovirus replication. Here, we show that mouse cytomegalovirus (MCMV) induces the expression of the FAM111 proteases and that FAM111B, but not FAM111A that has previously been shown to restrict the replication of polyomavirus and orthopoxvirus host range mutants, acts as a cellular factor suppressing MCMV replication in human and rhesus monkey cells. The identification of FAM111B as a host range factor should provide new insight into the physiological functions of this poorly characterized protein.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0134924"},"PeriodicalIF":4.0,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11650971/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569053","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":"Identification and characterization of host factor VCPIP1 as a multi-functional positive regulator of hepatitis B virus.","authors":"Ning Kang, Nannan Liu, Mu Liu, Shimei Zhang, Yang Yang, Jia Hou, Dan Tan, Zixiang Gao, Youhua Xie, Zhongliang Shen, Jing Liu","doi":"10.1128/jvi.01581-24","DOIUrl":"10.1128/jvi.01581-24","url":null,"abstract":"<p><p>Chronic infection with hepatitis B virus (HBV) remains an important public health challenge. Viral covalently closed circular DNA (cccDNA) persists in infected hepatocytes and serves as the template for transcribing all viral RNA species. HBV regulatory protein X (HBx) interacts with other viral and cellular proteins to play diverse functions in viral life cycle, including modulation of cccDNA transcription activity. Here, we used proximity labeling coupled with proteomic analysis to screen for HBx-interacting host proteins. One of the identified candidates, deubiquitinating enzyme valosin-containing protein-interacting protein 1 (VCPIP1), directly binds HBx and stabilizes HBx by reducing its proteasomal degradation, which corroborated a recent report. VCPIP1-mediated upregulation of HBV transcription, antigen expression, and genome replication was demonstrated using a series of HBV replication and infection models. More importantly, VCPIP1 was found to upregulate HBV in the absence of HBx. Mechanistic studies revealed that VCPIP1 HBx-independently associates with HBV enhancer I/X promoter (EnI/Xp) and positively modulates both its promoter and enhancer activities, partially through promoting the binding of YY1 transcription factor to EnI/Xp. Results presented here expand the recently described role of VCPIP1 in HBV life cycle and establish it as a multi-functional positive regulator of this virus.</p><p><strong>Importance: </strong>Hepatitis B virus (HBV) encodes the regulatory protein HBx that plays crucial roles in viral life cycle and cellular processes through interacting with viral and cellular proteins. Identifying HBx-interacting proteins may reveal novel aspects of host-virus interactions. In this work, proximity labeling coupled with proteomic analysis identified multiple HBx-interacting host factors, and among these, valosin-containing protein-interacting protein 1 (VCPIP1) was confirmed to directly bind HBx and reduce its proteasomal degradation, corroborating a recent report. In addition to upregulating HBx-expressing HBV, we showed that VCPIP1 also positively regulates mutant HBV lacking HBx expression. This novel HBx-independent function of VCPIP1 was shown to involve its association with one viral promoter/enhancer element, which upregulated the latter's promoter and enhancer activities. These results establish VCPIP1 as a positive regulator of HBV that acts through multiple, diverse mechanisms and might also contribute toward revealing novel cellular functions of VCPIP1.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0158124"},"PeriodicalIF":4.0,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11650987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569069","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":"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":"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":" ","pages":"e0160724"},"PeriodicalIF":4.0,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11650982/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"2018-2019 human seasonal H3N2 influenza A virus spillovers into swine with demonstrated virus transmission in pigs were not sustained in the pig population.","authors":"Joshua D Powell, Megan N Thomas, Tavis K Anderson, Michael A Zeller, Phillip C Gauger, Amy L Vincent Baker","doi":"10.1128/jvi.00087-24","DOIUrl":"10.1128/jvi.00087-24","url":null,"abstract":"<p><p>Human seasonal H3 clade 3C3a influenza A viruses (IAV) were detected four times in U.S. pigs from commercial swine farms in Michigan, Illinois, and Virginia in 2019. To evaluate the relative risk of this spillover to the pig population, whole genome sequencing and phylogenetic characterization were conducted, and the results revealed that all eight viral gene segments were closely related to 2018-2019 H3N2 human seasonal IAV. Next, a series of <i>in vitro</i> viral kinetics, receptor binding, and antigenic characterization studies were performed using a representative A/swine/Virginia/A02478738/2018(H3N2) (SW/VA/19) isolate. Viral replication kinetic studies of SW/VA/19 demonstrated less efficient replication curves than all 10 swine H3N2 viruses tested but higher than three human H3N2 strains. Serial passaging experiments of SW/VA/19 in swine cells did not increase virus replication, but changes at HA amino acid positions 9 and 159 occurred. In swine transmission studies, wild-type SW/VA/19 was shed in nasal secretions and transmitted to all indirect contact pigs, whereas the human seasonal strain A/Switzerland/9715293/2013(H3N2) from the same 3C3a clade failed to transmit. SW/VA/19 induced minimal macroscopic and microscopic lung lesions. Collectively, these findings demonstrate that these human seasonal H3N2 3C3a-like viruses did not require reassortment with endemic swine IAV gene segments for virus shedding and transmission in pigs. Limited detections in the U.S. pig population in the subsequent period of time suggest a yet-unknown restriction factor likely limiting the spread of these viruses in the U.S. pig population.IMPORTANCEInterspecies human-to-swine IAV transmission occurs globally and contributes to increased IAV diversity in pig populations. We present data that a swine isolate from a 2018-2019 human-to-swine transmission event was shed for multiple days in challenged and contact pigs. By characterizing this introduction through bioinformatic, molecular, and animal experimental approaches, these findings better inform animal health practices and vaccine decision-making. Since wholly human seasonal H3N2 viruses in the United States were not previously identified as being transmissible in pigs (i.e., reverse zoonosis), these findings reveal that the interspecies barriers for transmission to pigs may not require significant changes to all human seasonal H3N2, although additional changes may be required for sustained transmission in swine populations.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0008724"},"PeriodicalIF":4.0,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11650985/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142622648","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":"Recombination across distant coronavirid species and genera is a rare event with distinct genomic features.","authors":"Juan Patiño-Galindo, Adolfo García-Sastre, Jens H Kuhn, Raul Rabadan, Gustavo Palacios","doi":"10.1128/jvi.01100-24","DOIUrl":"10.1128/jvi.01100-24","url":null,"abstract":"<p><p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; family <i>Coronaviridae</i>, genus <i>Betacoronavirus</i>, subgenus <i>Sarbecovirus</i>) has caused millions of deaths, prompting a need for better understanding of coronavirid emergence and spillover to humans. As an evaluation of how some features of SARS-CoV-2, unique among sarbecoviruses, may have been acquired from related viruses, we conducted phylogenetic and recombination analyses to compare the frequency of recombination among coronavirids across vs within genera, subgenera, and species. Among known betacoronaviruses, we identified 199 (183 intraspecies, 16 interspecies, but no intersubgenera) recombination events. Phylogenetic analyses revealed that the ancestry of interspecies events was limited and less prone to affect 5' regions of coronavirid genome open reading frame 1 (ORF1) than intraspecies events. On the contrary, interspecies events were significantly more prone to impact the 3' end (ORF6-ORF8 and the nucleocapsid protein [<i>N</i>] ORF), suggesting the existence of region-specific constraints on recombination. This work substantiated that recombination among betacoronaviruses is limited by the genome similarity between their parental viruses. We conclude that SARS-CoV-2 likely acquired unique features through recombination with closely related circulating sarbecoviruses (most likely from the same species) that co-existed geographically.</p><p><strong>Importance: </strong>Understanding the evolutionary events that led to SARS-CoV-2 emergence, spillover, and spread is crucial to prevent, or at least be prepared for, the same type of occurrence in the future. Given that SARS-CoV-2 has some characteristics not found in other closely related viruses, we aimed to systematically assess how likely these unique features may have been acquired through recombination. We found that, although recombination is a frequent phenomenon among betacoronaviruses, it is mostly limited to closely related members of the same species. Therefore, we conclude that the most likely scenario involved feature acquisition from recombination with a closely related virus that was circulating in a geographically overlapping area or through a different biological process, but not recombination from a virus of a different species, genus, or subgenus.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0110024"},"PeriodicalIF":4.0,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11650996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668432","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":"Identification of stimuli that enhance human herpesvirus 6A (HHV-6A) replication and reconstitution.","authors":"Jana Reich, Dilan Serdar, Ann-Christin Weißmann, Benedikt B Kaufer","doi":"10.1128/jvi.01485-24","DOIUrl":"10.1128/jvi.01485-24","url":null,"abstract":"<p><p>Despite the availability of bacterial artificial chromosome (BAC) systems for human herpesvirus 6A (HHV-6A), reconstitution of infectious viruses is very challenging and time consuming. In this study, we developed approaches to improve the reconstitution process and enhance virus replication to overcome these technical challenges. Using dimethyl sulfoxide and exonuclease V, we significantly increased the efficiency of BAC transfections into JJHan T cells. We tested several stimulation strategies to enhance lytic replication and identified mitogens and glucocorticoids that, in combination, improve virus replication. In addition, we demonstrated that the interferon-mediated response impairs virus reconstitution and that the JAK1/JAK2 inhibitor ruxolitinib resulted in an immense improvement. Furthermore, hypoxia-inducible factor 1 alpha stabilization by IOX2 drastically accelerated virus reconstitution, indicating that the hypoxic response is a crucial regulator of HHV-6A replication. Our study sheds light on strategic approaches that improve replication and reconstitution of this ubiquitous human herpesvirus.</p><p><strong>Importance: </strong>HHV-6A is a betaherpesvirus that infects a wide range of human tissues and establishes lifelong latency in the host. Its reactivation has been implicated in several diseases, including multiple sclerosis, encephalitis, myocarditis, and chronic fatigue syndrome, although its pathogenetic role remains elusive. The efficacy of common antiviral drugs is limited, and no specific drugs target HHV-6A infection. The data of this study shed light on stimuli and potential pathways that influence HHV-6A replication and reconstitution. Our strategies not only simplify virus propagation and reconstitution to study HHV-6A biology but also provide the basis for the development of therapeutic strategies.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0148524"},"PeriodicalIF":4.0,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11651002/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603301","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}