44 results on '"TAO WANG"'
Search Results
2. The A137R Protein of African Swine Fever Virus Inhibits Type I Interferon Production via the Autophagy-Mediated Lysosomal Degradation of TBK1
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Maowen Sun, Shaoxiong Yu, Hailiang Ge, Tao Wang, Yongfeng Li, Pingping Zhou, Li Pan, Yu Han, Yuying Yang, Yuan Sun, Su Li, Lian-Feng Li, and Hua-Ji Qiu
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Virulence ,Swine ,viruses ,animal diseases ,Immunology ,Membrane Proteins ,Interferon-beta ,Protein Serine-Threonine Kinases ,Microbiology ,African Swine Fever Virus ,Nucleotidyltransferases ,Viral Proteins ,Virology ,Insect Science ,Macrophages, Alveolar ,Autophagy ,Animals ,African Swine Fever ,Lysosomes - Abstract
African swine fever is a lethal hemorrhagic disease of pigs caused by African swine fever virus (ASFV), which greatly threatens the pig industry in many countries. Deletion of virulence-associated genes to develop live attenuated ASF vaccines is considered to be a promising strategy. A recent study has revealed that the
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- 2022
3. ARF1 with Sec7 Domain-Dependent GBF1 Activates Coatomer Protein I To Support Classical Swine Fever Virus Entry
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Liang Zhang, Tao Wang, Yanyan Yi, Mengzhao Song, Mingxing Jin, Kangkang Guo, and Yanming Zhang
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ADP-Ribosylation Factors ,Swine ,Immunology ,Endothelial Cells ,Virus Internalization ,Virus Replication ,Coatomer Protein ,Microbiology ,Classical Swine Fever ,Cholesterol ,Classical Swine Fever Virus ,Virology ,Insect Science ,Animals ,Guanine Nucleotide Exchange Factors - Abstract
Classical swine fever (CSF), a highly contact-infectious disease caused by classical swine fever virus (CSFV) infecting domestic pigs or wild boars, has caused huge economic losses to the pig industry. Our previous studies have revealed that GBF1 and class I and II ARFs are required for CSFV proliferation.
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- 2022
4. Deletion of the H240R Gene of African Swine Fever Virus Decreases Infectious Progeny Virus Production Due to Aberrant Virion Morphogenesis and Enhances Inflammatory Cytokine Expression in Porcine Macrophages
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Yuan Sun, Hua-Ji Qiu, Lian-Feng Li, Bing Wang, Tao Wang, Kehui Zhang, Su Li, Lijie Tang, Miao Li, and Pingping Zhou
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Immunoelectron microscopy ,Immunology ,Mutant ,DNA virus ,Biology ,biology.organism_classification ,Microbiology ,Virology ,African swine fever virus ,Virus ,Proinflammatory cytokine ,Capsid ,Viral life cycle ,Insect Science - Abstract
African swine fever virus (ASFV) is a complex nucleocytoplasmic large DNA virus that causes African swine fever, a lethal hemorrhagic disease that currently threatens the pig industry. Recent studies have identified the viral structural proteins of infectious ASFV particles. However, the functional roles of several ASFV structural proteins remain largely unknown. Here, we characterized the function of the ASFV structural protein H240R (pH240R) in virus morphogenesis. pH240R was identified as a capsid protein using immunoelectron microscopy and interacted with the major capsid protein p72 by pulldown assays. Using a recombinant ASFV, ASFV-ΔH240R, with the H240R gene deletion from the wild-type ASFV (ASFV-WT) genome, we revealed that the infectious progeny virus titers were reduced by approximately 2.0 logs compared with ASFV-WT. Furthermore, we demonstrated that the growth defect was due to the generation of non-infectious particles with a high particle-to-infectious titer ratio in ASFV-ΔH240R-infected porcine primary alveolar macrophages (PAMs) than those of ASFV WT. Importantly, we found that pH240R did not affect virus-cell binding, endocytosis or egress but ASFV assembly; non-infectious virions containing large aberrant tubular and bilobulate structures, occupied nearly 98% of all virions were observed in ASFV-ΔH240R-infected PAMs by electron microscopy. Notably, we demonstrated that ASFV-ΔH240R infection induced high-level inflammatory cytokines expression in PAMs. Collectively, we show for the first time that pH240R is essential for ASFV icosahedral capsid formation and infectious particle production. Also, these results highlight the importance of pH240R in ASFV morphogenesis and provide a novel target for the development of ASF vaccines and antivirals. IMPORTANCE African swine fever is a lethal hemorrhagic disease of global concern that is caused by African swine fever virus (ASFV). Despite extensive research, there exist relevant gaps in knowledge of the fundamental biology of the viral life cycle. In this study, we identified pH240R as a capsid protein that interacts with the major capsid protein p72. Furthermore, we showed that pH240R was required for the efficient production of infectious progeny virus as indicated by the H240R-deleted ASFV mutant (ASFV-ΔH240R). More specifically, pH240R directs the morphogenesis of ASFV toward the icosahedral capsid in the process of assembly. In addition, ASFV-ΔH240R infection induced high-level inflammatory cytokines expression in porcine primary alveolar macrophages. Our results elucidate the role of pH240R in the process of ASFV assembly, which may instruct future research on effective vaccines or antiviral strategies.
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- 2022
5. Orsay Virus CP-δ Adopts a Novel β-Bracelet Structural Fold and Incorporates into Virions as a Head Fiber
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David Wang, Weiwei Zhong, Yanlin Fan, Ying Zhou, Matthew V. Holt, Miao Jin, Yusong R. Guo, Yizhi Jane Tao, Tao Wang, Hongbing Jiang, Jim L. Zhang, and Nicolas L. Young
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Models, Molecular ,Protein Conformation, alpha-Helical ,Caenorhabditis briggsae ,Sequence analysis ,β-bracelet ,viruses ,Genetic Vectors ,Immunology ,Scleroproteins ,Gene Expression ,Biology ,Crystallography, X-Ray ,medicine.disease_cause ,Microbiology ,Host Specificity ,Virus ,Viral Proteins ,Virology ,Escherichia coli ,Orsay virus ,medicine ,Animals ,Nodaviridae ,Protein Interaction Domains and Motifs ,Amino Acid Sequence ,Cloning, Molecular ,Caenorhabditis elegans ,crystallography ,Polyproteins ,Coiled coil ,Sequence Homology, Amino Acid ,Structure and Assembly ,Virion ,biology.organism_classification ,Fusion protein ,Recombinant Proteins ,Cell biology ,Capsid ,Insect Science ,Capsid Proteins ,Protein Conformation, beta-Strand ,viral fiber ,Sequence Alignment - Abstract
Viruses often have extended fibers to mediate host cell recognition and entry, serving as promising targets for antiviral drug development. Unlike other known viral fibers, the δ proteins from the three recently discovered nematode viruses are incorporated into infectious particles as protruding fibers covalently linked to the capsid. Crystal structures of δ revealed novel pentameric folding repeats, which we term β-bracelets, in the intermediate shaft region. Based on sequence analysis, the β-bracelet motif of δ is conserved in all three nematode viruses and could account for ∼60% of the total length of the fiber. Our study indicated that δ plays important roles in cell attachment for this group of nematode viruses. In addition, the tightly knitted β-bracelet fold, which presumably allows δ to survive harsh environments in the worm gut, could be applicable to bioengineering applications given its potentially high stability., Fiber proteins are commonly found in eukaryotic and prokaryotic viruses, where they play important roles in mediating viral attachment and host cell entry. They typically form trimeric structures and are incorporated into virions via noncovalent interactions. Orsay virus, a small RNA virus which specifically infects the laboratory model nematode Caenorhabditis elegans, encodes a fibrous protein δ that can be expressed as a free protein and as a capsid protein-δ (CP-δ) fusion protein. Free δ has previously been demonstrated to facilitate viral exit following intracellular expression; however, the biological significance and prevalence of CP-δ remained relatively unknown. Here, we demonstrate that Orsay CP-δ is covalently incorporated into infectious particles, the first example of any attached viral fibers known to date. The crystal structure of δ(1–101) (a deletion mutant containing the first 101 amino acid [aa] residues of δ) reveals a pentameric, 145-Å long fiber with an N-terminal coiled coil followed by multiple β-bracelet repeats. Electron micrographs of infectious virions depict particle-associated CP-δ fibers with dimensions similar to free δ. The δ proteins from two other nematode viruses, Le Blanc and Santeuil, which both specifically infect Caenorhabditis briggsae, were also found to form fibrous molecules. Recombinant Le Blanc δ was able to block Orsay virus infection in worm culture and vice versa, suggesting these two viruses likely compete for the same cell receptor(s). Thus, we propose that while CP-δ likely mediates host cell attachment for all three nematode viruses, additional downstream factor(s) ultimately determine the host specificity and range of each virus. IMPORTANCE Viruses often have extended fibers to mediate host cell recognition and entry, serving as promising targets for antiviral drug development. Unlike other known viral fibers, the δ proteins from the three recently discovered nematode viruses are incorporated into infectious particles as protruding fibers covalently linked to the capsid. Crystal structures of δ revealed novel pentameric folding repeats, which we term β-bracelets, in the intermediate shaft region. Based on sequence analysis, the β-bracelet motif of δ is conserved in all three nematode viruses and could account for ∼60% of the total length of the fiber. Our study indicated that δ plays important roles in cell attachment for this group of nematode viruses. In addition, the tightly knitted β-bracelet fold, which presumably allows δ to survive harsh environments in the worm gut, could be applicable to bioengineering applications given its potentially high stability.
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- 2020
6. cis -Acting Sequences and Secondary Structures in Untranslated Regions of Duck Tembusu Virus RNA Are Important for Cap-Independent Translation and Viral Proliferation
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Ying Wu, Shaqiu Zhang, Yunya Liu, Shun Chen, Qiao Yang, Renyong Jia, Mingshu Wang, Yuanyuan Wu, Dekang Zhu, Mafeng Liu, Anchun Cheng, Yanling Yu, Xinxin Zhao, Andres Merits, Leichang Pan, Ling Zhang, and Tao Wang
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Untranslated region ,viruses ,Immunology ,RNA ,Translation (biology) ,Biology ,biology.organism_classification ,Microbiology ,Genome ,Virology ,Virus ,Genome Replication and Regulation of Viral Gene Expression ,Open reading frame ,Internal ribosome entry site ,Flavivirus ,Insect Science - Abstract
Duck Tembusu virus (DTMUV) (genus Flavivirus) is a causative agent of duck egg drop syndrome and has zoonotic potential. The positive-strand RNA genomes of flaviviruses are commonly translated in a cap-dependent manner. However, dengue and Zika viruses also exhibit cap-independent translation. In this study, we show that RNAs containing 5′ and 3′ untranslated regions (UTRs) of DTMUV, mosquito-borne Tembusu virus (TMUV), and Japanese encephalitis virus can be translated in a cap-independent manner in mammalian, avian, and mosquito cells. The ability of the 5′ UTRs of flaviviruses to direct the translation of a second open reading frame in bicistronic RNAs was much less than that observed for internal ribosome entry site (IRES) encephalomyocarditis virus, indicating a lack of substantial IRES activity. Instead, cap-independent translation of DTMUV RNA was dependent on the presence of a 3′ UTR, RNA secondary structures located in both UTRs, and specific RNA sequences. Mutations inhibiting cap-independent translation decreased DTMUV proliferation in vitro and delayed, but did not prevent, the death of infected duck embryos. Thus, the 5′ and 3′ UTRs of DTMUV enable the virus to use a cap- and IRES-independent RNA genome translation strategy that is important for its propagation and virulence. IMPORTANCE The genus Flavivirus includes major human pathogens, as well as animal-infecting viruses with zoonotic potential. In order to counteract the threats these viruses represent, it is important to understand their basic biology to develop universal attenuation strategies. Here, we demonstrate that five different flaviviruses use cap-independent translation, indicating that the phenomenon is probably common to all members of the genus. The mechanism used for flavivirus cap-independent translation was found to be different from that of IRES-mediated translation and dependent on both 5′ and 3′ UTRs that act in cis. As cap-independent translation was also observed in mosquito cells, its role in flavivirus infection is unlikely to be limited to the evasion of consequences of the shutoff of host translation. We found that the inhibition of cap-independent translation results in decreased viral proliferation, indicating that the strategy could be applied to produce attenuated variants of flaviviruses as potential vaccine candidates.
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- 2020
7. The Severe Fever with Thrombocytopenia Syndrome Virus NSs Protein Interacts with CDK1 To Induce G 2 Cell Cycle Arrest and Positively Regulate Viral Replication
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Leling Xu, Tao Wang, Wen Hou, Sihua Liu, Zhiyun Wang, Keke Zhang, Xueping Li, Hongyun Liu, and Jun Kang
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Phlebovirus ,Cell cycle checkpoint ,Viral protein ,Immunology ,Viral Nonstructural Proteins ,Biology ,Bunyaviridae Infections ,Virus Replication ,medicine.disease_cause ,Microbiology ,Virus ,Interferon ,Virology ,CDC2 Protein Kinase ,medicine ,Humans ,Cyclin B1 ,Cyclin-dependent kinase 1 ,Hep G2 Cells ,Cell cycle ,Virus-Cell Interactions ,G2 Phase Cell Cycle Checkpoints ,HEK293 Cells ,Viral replication ,Insect Science ,HeLa Cells ,medicine.drug ,Severe fever with thrombocytopenia syndrome virus - Abstract
Severe fever with thrombocytopenia syndrome virus (SFTSV) is a newly identified phlebovirus associated with severe hemorrhagic fever in humans. While many viruses subvert the host cell cycle to promote viral growth, it is unknown whether this is a strategy employed by SFTSV. In this study, we investigated how SFTSV manipulates the cell cycle and the effect of the host cell cycle on SFTSV replication. Our results suggest that cells arrest at the G(2)/M transition following infection with SFTSV. The accumulation of cells at the G(2)/M transition did not affect virus adsorption and entry but did facilitate viral replication. In addition, we found that SFTSV NSs, a nonstructural protein that forms viroplasm-like structures in the cytoplasm of infected cells and promotes virulence by modulating the interferon response, induces a large number of cells to arrest at the G(2)/M transition by interacting with CDK1. The interaction between NSs and CDK1, which is inclusion body dependent, inhibits formation and nuclear import of the cyclin B1-CDK1 complex, thereby leading to cell cycle arrest. Expression of a CDK1 loss-of-function mutant reversed the inhibitive effect of NSs on the cell cycle, suggesting that this protein is a potential antiviral target. Our study provides new insight into the role of a specific viral protein in SFTSV replication, indicating that NSs induces G(2)/M arrest of SFTSV-infected cells, which promotes viral replication. IMPORTANCE Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne pathogen that causes severe hemorrhagic fever. Although SFTSV poses a serious threat to public health and was recently isolated, its pathogenesis remains unclear. In particular, the relationship between SFTSV infection and the host cell cycle has not been described. Here, we show for the first time that both asynchronized and synchronized SFTSV-susceptible cells arrest at the G(2)/M checkpoint following SFTSV infection and that the accumulation of cells at this checkpoint facilitates viral replication. We also identify a key mechanism underlying SFTSV-induced G(2)/M arrest, in which SFTSV NSs interacts with CDK1 to inhibit formation and nuclear import of the cyclin B1-CDK1 complex, thus preventing it from regulating cell cycle progression. Our study highlights the key role that NSs plays in SFTSV-induced G(2)/M arrest.
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- 2020
8. Typical Stress Granule Proteins Interact with the 3' Untranslated Region of Enterovirus D68 To Inhibit Viral Replication
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Shuai Gao, Jinyan Cheng, Zhiyun Wang, Cheng Zhu, Jun Kang, Tao Wang, Jinyu Li, and Sihua Liu
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Untranslated region ,Cytoplasm ,Immunology ,Biology ,Cytoplasmic Granules ,Virus Replication ,Microbiology ,Virus ,ELAV-Like Protein 1 ,Stress granule ,Antigen ,Virology ,Cell Line, Tumor ,Humans ,Phosphorylation ,RNA, Small Interfering ,Poly-ADP-Ribose Binding Proteins ,3' Untranslated Regions ,Enterovirus D, Human ,Innate immune system ,Three prime untranslated region ,DNA Helicases ,Protein kinase R ,Cell biology ,T-Cell Intracellular Antigen-1 ,Virus-Cell Interactions ,HEK293 Cells ,RNA Recognition Motif Proteins ,Viral replication ,A549 Cells ,Insect Science ,RNA, Viral ,RNA Helicases ,HeLa Cells - Abstract
Stress granules (SGs) are formed in the cytoplasm under environmental stress, including viral infection. Human enterovirus D68 (EV-D68) is a highly pathogenic virus which can cause serious respiratory and neurological diseases. At present, there is no effective drug or vaccine against EV-D68 infection, and the relationship between EV-D68 infection and SGs is poorly understood. This study revealed the biological function of SGs in EV-D68 infection. Our results suggest that EV-D68 infection induced the accumulation of SG marker proteins Ras GTPase-activated protein-binding protein 1 (G3BP1), T cell intracellular antigen 1 (TIA1), and human antigen R (HUR) in the cytoplasm of infected host cells during early infection but inhibited their accumulation during the late stage. Simultaneously, we revealed that EV-D68 infection induces HUR, TIA1, and G3BP1 colocalization, which marks the formation of typical SGs dependent on protein kinase R (PKR) and eIF2α phosphorylation. In addition, we found that TIA1, HUR, and G3BP1 were capable of targeting the 3′ untranslated regions (UTRs) of EV-D68 RNA to inhibit viral replication. However, the formation of SGs in response to arsenite (Ars) gradually decreased as the infection progressed, and G3BP1 was cleaved in the late stage as a strategy to antagonize SGs. Our findings have important implications in understanding the mechanism of interaction between EV-D68 and the host while providing a potential target for the development of antiviral drugs. IMPORTANCE EV-D68 is a serious threat to human health, and there are currently no effective treatments or vaccines. SGs play an important role in cellular innate immunity as a target with antiviral effects. This manuscript describes the formation of SGs induced by EV-D68 early infection but inhibited during the late stage of infection. Moreover, TIA1, HUR, and G3BP1 can chelate a specific site of the 3′ UTR of EV-D68 to inhibit viral replication, and this interaction is sequence and complex dependent. However, this inhibition can be antagonized by overexpression of the minireplicon. These findings increase our understanding of EV-D68 infection and may help identify new antiviral targets that can inhibit viral replication and limit the pathogenesis of EV-D68.
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- 2019
9. Binding of Duck Tembusu Virus Nonstructural Protein 2A to Duck STING Disrupts Induction of Its Signal Transduction Cascade To Inhibit Beta Interferon Induction
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Qiao Yang, Wei Zhang, Yunya Liu, Yuanyuan Wu, Renyong Jia, Xinxin Zhao, Miao Zeng, Zhen Wu, Bowen Jiang, Anchun Cheng, Yanping Duan, Yanling Yu, Ying Wu, Shun Chen, Leichang Pan, Dekang Zhu, Shaqiu Zhang, Mafeng Liu, Tao Wang, Mingshu Wang, and Ling Zhang
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Interferon Regulatory Factor-7 ,Immunology ,Biology ,Protein Serine-Threonine Kinases ,Viral Nonstructural Proteins ,Southeast asian ,Microbiology ,Virus ,Cell Line ,Flavivirus Infections ,Viral Proteins ,Interferon ,Virology ,medicine ,Animals ,Humans ,Innate immune system ,Flavivirus ,Membrane Proteins ,MDA5 ,Interferon-beta ,Immunity, Innate ,Virus-Cell Interactions ,Ducks ,Insect Science ,Stimulator of interferon genes ,IRF7 ,Interferons ,Interferon regulatory factors ,medicine.drug ,Signal Transduction - Abstract
Duck Tembusu virus (DTMUV), which is similar to other mosquito-borne flaviviruses that replicate well in most mammalian cells, is an emerging pathogenic flavivirus that has caused epidemics in egg-laying and breeding waterfowl. Immune organ defects and neurological dysfunction are the main clinical symptoms of DTMUV infection. Preinfection with DTMUV makes the virus impervious to later interferon (IFN) treatment, revealing that DTMUV has evolved some strategies to defend against host IFN-dependent antiviral responses. Immune inhibition was further confirmed by screening for DTMUV-encoded proteins, which suggested that NS2A significantly inhibited IFN-β and IFN-stimulated response element (ISRE) promoter activity in a dose-dependent manner and facilitated reinfection with duck plague virus (DPV). DTMUV NS2A was able to inhibit duck retinoic acid-inducible gene-I (RIG-I)-, and melanoma differentiation-associated gene 5 (MDA5)-, mitochondrial-localized adaptor molecules (MAVS)-, stimulator of interferon genes (STING)-, and TANK-binding kinase 1 (TBK1)-induced IFN-β transcription, but not duck TBK1- and interferon regulatory factor 7 (IRF7)-mediated effective phases of IFN response. Furthermore, we found that NS2A competed with duTBK1 in binding to duck STING (duSTING), impaired duSTING-duSTING binding, and reduced duTBK1 phosphorylation, leading to the subsequent inhibition of IFN production. Importantly, we first identified that the W164A, Y167A, and S361A mutations in duSTING significantly impaired the NS2A-duSTING interaction, which is important for NS2A-induced IFN-β inhibition. Hence, our data demonstrated that DTMUV NS2A disrupts duSTING-dependent antiviral cellular defenses by binding with duSTING, which provides a novel mechanism by which DTMUV subverts host innate immune responses. The potential interaction sites between NS2A and duSTING may be the targets of future novel antiviral therapies and vaccine development. IMPORTANCE Flavivirus infections are transmitted through mosquitos or ticks and lead to significant morbidity and mortality worldwide with a spectrum of manifestations. Infection with an emerging flavivirus, DTMUV, manifests with clinical symptoms that include lesions of the immune organs and neurological dysfunction, leading to heavy egg drop and causing serious harm to the duck industry in China, Thailand, Malaysia, and other Southeast Asian countries. Mosquito cells, bird cells, and mammalian cell lines are all susceptible to DTMUV infection. An in vivo study revealed that BALB/c mice and Kunming mice were susceptible to DTMUV after intracerebral inoculation. Moreover, there are no reports about DTMUV-related human disease, but antibodies against DTMUV and viral RNA were detected in serum samples of duck industry workers. This information implies that DTMUV has expanded its host range and may pose a threat to mammalian health. However, the pathogenesis of DTMUV is largely unclear. Our results show that NS2A strongly blocks the STING-induced signal transduction cascade by binding with STING, which subsequently blocks STING-STING binding and TBK1 phosphorylation. More importantly, the W164, Y167, or S361 residues in duSTING were identified as important interaction sites between STING and NS2A that are vital for NS2A-induced IFN production and effective phases of IFN response. Uncovering the mechanism by which DTMUV NS2A inhibits IFN in the cells of its natural hosts, ducks, will help us understand the role of NS2A in DTMUV pathogenicity.
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- 2019
10. Programmed −2/−1 Ribosomal Frameshifting in Simarteriviruses: an Evolutionarily Conserved Mechanism
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Yíngyún Caì, Tao Wang, Sawsan Napthine, Jens H. Kuhn, Ian Brierley, Xingyu Yan, Ying Fang, Andrew E. Firth, Yanhua Li, Firth, Andrew E [0000-0002-7986-9520], and Apollo - University of Cambridge Repository
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Models, Molecular ,Simian hemorrhagic fever virus ,Arterivirus ,Sequence analysis ,Viral protein ,Protein Conformation ,Amino Acid Motifs ,Immunology ,Gene Expression ,Viral Nonstructural Proteins ,Slippery sequence ,medicine.disease_cause ,Virus Replication ,Microbiology ,Cell Line ,03 medical and health sciences ,Structure-Activity Relationship ,Virology ,medicine ,−2/−1 programmed ribosomal frameshifting ,Animals ,Porcine respiratory and reproductive syndrome virus ,Amino Acid Sequence ,030304 developmental biology ,Genetics ,0303 health sciences ,Translational frameshift ,biology ,030306 microbiology ,Frameshifting, Ribosomal ,biology.organism_classification ,Porcine reproductive and respiratory syndrome virus ,Biological Evolution ,digestive system diseases ,3. Good health ,Genome Replication and Regulation of Viral Gene Expression ,Viral replication ,Insect Science ,simarterivirus - Abstract
Simarteriviruses are a group of arteriviruses infecting nonhuman primates, and a number of new species have been established in recent years. Although these arteriviruses are widely distributed among African nonhuman primates of different species, and some of them cause lethal hemorrhagic fever disease, this group of viruses has been undercharacterized. Since wild nonhuman primates are historically important sources or reservoirs of human pathogens, there is concern that simarteriviruses may be preemergent zoonotic pathogens. Thus, molecular characterization of simarteriviruses is becoming a priority in arterivirology. In this study, we demonstrated that an evolutionarily conserved ribosomal frameshifting mechanism is used by simarteriviruses and other distantly related arteriviruses for the expression of additional viral proteins. This mechanism is unprecedented in eukaryotic systems. Given the crucial role of ribosome function in all living systems, the potential impact of the in-depth characterization of this novel mechanism reaches beyond the field of virology., The −2/−1 programmed ribosomal frameshifting (−2/−1 PRF) mechanism in porcine reproductive and respiratory syndrome virus (PRRSV) leads to the translation of two additional viral proteins, nonstructural protein 2TF (nsp2TF) and nsp2N. This −2/−1 PRF mechanism is transactivated by a viral protein, nsp1β, and cellular poly(rC) binding proteins (PCBPs). Critical elements for −2/−1 PRF, including a slippery sequence and a downstream C-rich motif, were also identified in 11 simarteriviruses. However, the slippery sequences (XXXUCUCU instead of XXXUUUUU) in seven simarteriviruses can only facilitate −2 PRF to generate nsp2TF. The nsp1β of simian hemorrhagic fever virus (SHFV) was identified as a key factor that transactivates both −2 and −1 PRF, and the universally conserved Tyr111 and Arg114 in nsp1β are essential for this activity. In vitro translation experiments demonstrated the involvement of PCBPs in simarterivirus −2/−1 PRF. Using SHFV reverse genetics, we confirmed critical roles of nsp1β, slippery sequence, and C-rich motif in −2/−1 PRF in SHFV-infected cells. Attenuated virus growth ability was observed in SHFV mutants with impaired expression of nsp2TF and nsp2N. Comparative genomic sequence analysis showed that key elements of −2/−1 PRF are highly conserved in all known arteriviruses except equine arteritis virus (EAV) and wobbly possum disease virus (WPDV). Furthermore, −2/−1 PRF with SHFV PRF signal RNA can be stimulated by heterotypic nsp1βs of all non-EAV arteriviruses tested. Taken together, these data suggest that −2/−1 PRF is an evolutionarily conserved mechanism employed in non-EAV/-WPDV arteriviruses for the expression of additional viral proteins that are important for viral replication. IMPORTANCE Simarteriviruses are a group of arteriviruses infecting nonhuman primates, and a number of new species have been established in recent years. Although these arteriviruses are widely distributed among African nonhuman primates of different species, and some of them cause lethal hemorrhagic fever disease, this group of viruses has been undercharacterized. Since wild nonhuman primates are historically important sources or reservoirs of human pathogens, there is concern that simarteriviruses may be preemergent zoonotic pathogens. Thus, molecular characterization of simarteriviruses is becoming a priority in arterivirology. In this study, we demonstrated that an evolutionarily conserved ribosomal frameshifting mechanism is used by simarteriviruses and other distantly related arteriviruses for the expression of additional viral proteins. This mechanism is unprecedented in eukaryotic systems. Given the crucial role of ribosome function in all living systems, the potential impact of the in-depth characterization of this novel mechanism reaches beyond the field of virology.
- Published
- 2019
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11. Acidity/Alkalinity of Japanese Encephalitis Virus E Protein Residue 138 Alters Neurovirulence in Mice
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Liwei Li, Zhiyong Ma, Xuchen Zheng, Tao Wang, Yafeng Qiu, Guangzhi Tong, Tongling Shan, Fei Gao, Hai Yu, Yan-Jun Zhou, Hao Zheng, Guoxin Li, and Wu Tong
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0301 basic medicine ,viruses ,Immunology ,Virulence ,Biology ,medicine.disease_cause ,Microbiology ,Virus ,Cell Line ,03 medical and health sciences ,Mice ,Viral Envelope Proteins ,Viral entry ,Virology ,Cricetinae ,medicine ,Animals ,Humans ,Amino Acid Sequence ,Encephalitis, Japanese ,Glycoproteins ,chemistry.chemical_classification ,Encephalitis Virus, Japanese ,Mutation ,Japanese encephalitis ,Hydrogen-Ion Concentration ,medicine.disease ,In vitro ,030104 developmental biology ,Acidity/alkalinity ,chemistry ,Amino Acid Substitution ,Insect Science ,Pathogenesis and Immunity ,Glycoprotein - Abstract
The Japanese encephalitis virus (JEV) envelope (E) protein, as one of mediators of virus entry into host cells, plays a critical role in determining virulence. The Glu-to-Lys mutation of residue 138 in E protein (E138) plays an important role in attenuating JEV vaccine strain SA14-14-2. However, it is not clear how E138 attenuates JEV. Here, we demonstrate that the Glu-to-Arg mutation of E138 also determines the attenuation of JEV strain 10S3. Likewise, for its parent strain (HEN0701), a virulence strain, the mutations of E138 are responsible for virulence alteration. Furthermore, we demonstrated that mutations of alkaline residues in E138 contributed to the attenuation of neurovirulence; in contrast, mutations of acidic residues enhanced the neurovirulence of the strains. Moreover, acidity in residue E47 had a similar effect on neurovirulence. Furthermore, the alkaline E138 residue enhanced susceptibility to heparin inhibition in vitro and limited JEV diffusion in mouse brain. These results suggest that the acidity/alkalinity of the E138 residue plays an important role in neurovirulence determination. IMPORTANCE The E protein is the only glycoprotein in mature JEV, and it plays an important role in viral neurovirulence. E protein mutations attenuate JEV neurovirulence through unclear mechanisms. Here, we discovered that E138 is a predominant determinant of JEV neurovirulence. We demonstrated that the alkalinity/acidity of E138 determines JEV neurovirulence. These data contribute to the characterization of the E protein and the rational development of novel JEV vaccines.
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- 2018
12. Association of Potent Human Antiviral Cytidine Deaminases with 7SL RNA and Viral RNP in HIV-1 Virions
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Wenyan Zhang, Kevin Yu, Xiao Fang Yu, Xiong Yong, Juan Du, and Tao Wang
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Protein Conformation ,viruses ,Amino Acid Motifs ,Blotting, Western ,Molecular Sequence Data ,Immunology ,RNA-dependent RNA polymerase ,HIV Infections ,Biology ,Kidney ,Antiviral Agents ,Polymerase Chain Reaction ,gag Gene Products, Human Immunodeficiency Virus ,Microbiology ,chemistry.chemical_compound ,Cytidine Deaminase ,Virology ,RNA, Small Cytoplasmic ,Animals ,Humans ,Immunoprecipitation ,Signal recognition particle RNA ,Amino Acid Sequence ,RNA, Messenger ,Cells, Cultured ,DNA Primers ,Viral matrix protein ,Sequence Homology, Amino Acid ,Reverse Transcriptase Polymerase Chain Reaction ,Virus Assembly ,Virion ,Ribonucleoprotein particle ,RNA ,Cytidine ,Non-coding RNA ,Virus-Cell Interactions ,Cell biology ,RNA silencing ,Ribonucleoproteins ,chemistry ,Insect Science ,HIV-1 ,RNA, Viral ,Signal Recognition Particle ,Plasmids - Abstract
7SL RNA promotes the formation of the signal recognition particle that targets secretory and membrane proteins to the endoplasmic reticulum. 7SL RNA is also selectively packaged by many retroviruses, including HIV-1. Here, we demonstrate that 7SL RNA is an integral component of the viral ribonucleoprotein (RNP) complex containing Gag, viral genomic RNA, and \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathbf{tRNA}_{3}^{Lys}\) \end{document} . Only the potent anti-HIV-1 cytidine deaminases can bind to 7SL RNA and target to HIV-1 RNP. A conserved motif in the amino-terminal region of A3G is important for 7SL RNA interaction. The weak anti-HIV-1 A3C did not interact with 7SL RNA and failed to target to viral RNPs, despite efficient virion packaging. However, a chimeric construct of A3C plus the 7SL-binding amino terminus of A3G did target to viral RNPs and showed enhanced anti-HIV-1 activity. 7SL RNA binding is a conserved feature of human anti-HIV-1 cytidine deaminases. Thus, potent anti-HIV-1 cytidine deaminases have evolved to possess a unique RNA-binding ability for precise HIV-1 targeting and viral inhibition.
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- 2010
13. HC-Pro Protein of Potato Virus Y Can Interact with Three Arabidopsis 20S Proteasome Subunits In Planta
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Yong-Sheng Jin, Changwang Deng, Dongyuan Ma, Jingchen Jin, Jiangli Dong, Daofeng Li, and Tao Wang
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Proteasome Endopeptidase Complex ,Protein subunit ,Potyvirus ,Immunology ,Mutant ,Arabidopsis ,Mutation, Missense ,Plasma protein binding ,Microbiology ,Viral Proteins ,Two-Hybrid System Techniques ,Virology ,Protein Interaction Mapping ,Plant Proteins ,Sequence Deletion ,chemistry.chemical_classification ,biology ,biology.organism_classification ,Yeast ,Virus-Cell Interactions ,N-terminus ,Cysteine Endopeptidases ,Enzyme ,Amino Acid Substitution ,Potato virus Y ,Biochemistry ,chemistry ,Insect Science ,Protein Binding - Abstract
The multifunctional protein helper component proteinase (HC-Pro) is thought to interfere with the activity of the 20S proteasome; however, no sites of interaction have been identified for either protein. Here, we first show that the Potato virus Y (PVY) HC-Pro protein can interact with three Arabidopsis 20S proteasome subunits (PAA, PBB, and PBE), using a yeast two-hybrid system and the bimolecular fluorescence complement assay. In addition, yeast two-hybrid analysis of the interaction between several mutant subunits of the 20S proteasome and PVY HC-Pro confirmed that residues 81 to 140 of PAA, 1 to 80 of PBB, and 160 to 274 of PBE are necessary for binding PAA, PBB, and PBE to PVY HC-Pro, respectively. Deletion mutant analysis of PVY HC-Pro showed that the N terminus (residues 1 to 97) is necessary for its interaction with three Arabidopsis 20S proteasome subunits. The ability of HC-Pro to interact and interfere with the activity of the 20S proteasome may help explain the molecular basis of its multifunctional character.
- Published
- 2007
14. Envelope Conformational Changes Induced by Human Immunodeficiency Virus Type 1 Attachment Inhibitors Prevent CD4 Binding and Downstream Entry Events
- Author
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Ira B. Dicker, Hua Fang, James E. Robinson, Pin-Fang Lin, John D. Matiskella, Brian McAuliffe, Nannan Zhou, Li Fan, Richard A. Dalterio, Paul R. Clapham, Gregory Yamanaka, John F. Kadow, Yi-Fei Gong, Richard J. Colonno, Tao Wang, Beata Nowicka-Sans, Chang-Ben Li, Yasutsugu Ueda, Hsu-Tso Ho, and Zhiwei Yin
- Subjects
Indoles ,Anti-HIV Agents ,Protein Conformation ,viruses ,Immunology ,HIV Envelope Protein gp120 ,Gp41 ,Microbiology ,Piperazines ,Virus ,Protein structure ,Viral entry ,Virion binding ,Virology ,Vaccines and Antiviral Agents ,Pyruvic Acid ,Humans ,Envelope (waves) ,biology ,Virion ,biology.organism_classification ,Molecular biology ,Cell biology ,Fostemsavir ,Insect Science ,CD4 Antigens ,Lentivirus ,HIV-1 ,HeLa Cells - Abstract
BMS-488043 is a small-molecule human immunodeficiency virus type 1 (HIV-1) CD4 attachment inhibitor with demonstrated clinical efficacy. The compound inhibits soluble CD4 (sCD4) binding to the 11 distinct HIV envelope gp120 proteins surveyed. Binding of BMS-488043 and that of sCD4 to gp120 are mutually exclusive, since increased concentrations of one can completely block the binding of the other without affecting the maximal gp120 binding capacity. Similarly, BMS-488043 inhibited virion envelope trimers from binding to sCD4-immunoglobulin G (IgG), with decreasing inhibition as the sCD4-IgG concentration increased, and BMS-488043 blocked the sCD4-induced exposure of the gp41 groove in virions. In both virion binding assays, BMS-488043 was active only when added prior to sCD4. Collectively, these results indicate that obstruction of gp120-sCD4 interactions is the primary inhibition mechanism of this compound and that compound interaction with envelope must precede CD4 binding. By three independent approaches, BMS-488043 was further shown to induce conformational changes within gp120 in both the CD4 and CCR5 binding regions. These changes likely prevent gp120-CD4 interactions and downstream entry events. However, BMS-488043 could only partially inhibit CD4 binding to an HIV variant containing a specific envelope truncation and altered gp120 conformation, despite effectively inhibiting the pseudotyped virus infection. Taken together, BMS-488043 inhibits viral entry primarily through altering the envelope conformation and preventing CD4 binding, and other downstream entry events could also be inhibited as a result of these induced conformational changes.
- Published
- 2006
15. Biochemical and Genetic Characterizations of a Novel Human Immunodeficiency Virus Type 1 Inhibitor That Blocks gp120-CD4 Interactions
- Author
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Ira B. Dicker, Ronald E. Rose, Nicholas A. Meanwell, Tao Wang, Brian McAuliffe, Li Fan, Pin-Fang Lin, Qi Guo, Nannan Zhou, David R. Langley, Hwei-Gene Heidi Wang, Hsu-Tso Ho, Richard J. Colonno, Helen Scarnati, Ralph Abraham, Hua Fang, and Jacques Friborg
- Subjects
Anti-HIV Agents ,viruses ,Immunology ,Binding pocket ,Human immunodeficiency virus (HIV) ,HIV Envelope Protein gp120 ,Biology ,medicine.disease_cause ,Binding, Competitive ,Microbiology ,Piperazines ,Cell Line ,Mice ,ANTIRETROVIRAL AGENTS ,Viral entry ,Cricetinae ,Virology ,Vaccines and Antiviral Agents ,medicine ,Animals ,Binding site ,Binding Sites ,virus diseases ,Cd4 receptors ,Cell biology ,Target site ,Cell culture ,Insect Science ,CD4 Antigens ,HIV-1 - Abstract
BMS-378806 is a recently discovered small-molecule human immunodeficiency virus type 1 (HIV-1) attachment inhibitor with good antiviral activity and pharmacokinetic properties. Here, we demonstrate that the compound targets viral entry by inhibiting the binding of the HIV-1 envelope gp120 protein to cellular CD4 receptors via a specific and competitive mechanism. BMS-378806 binds directly to gp120 at a stoichiometry of approximately 1:1, with a binding affinity similar to that of soluble CD4. The potential BMS-378806 target site was localized to a specific region within the CD4 binding pocket of gp120 by using HIV-1 gp120 variants carrying either compound-selected resistant substitutions or gp120-CD4 contact site mutations. Mapping of resistance substitutions to the HIV-1 envelope, and the lack of compound activity against a CD4-independent viral infection confirm the gp120-CD4 interactions as the target in infected cells. BMS-378806 therefore serves as a prototype for this new class of antiretroviral agents and validates gp120 as a viable target for small-molecule inhibitors.
- Published
- 2003
16. Mink Cell Focus-Forming Murine Leukemia Virus Infection Induces Apoptosis of Thymic Lymphocytes
- Author
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Tao Wang, Fayth K. Yoshimura, Fei Yu, Jerrold R. Turner, and Hyeong Reh Choi Kim
- Subjects
CD4-Positive T-Lymphocytes ,T-Lymphocytes ,viruses ,CD3 ,Immunology ,Apoptosis ,DNA Fragmentation ,Thymus Gland ,CD8-Positive T-Lymphocytes ,medicine.disease_cause ,Microbiology ,Virus ,Mice ,Mice, Inbred AKR ,Mink Cell Focus-Inducing Viruses ,Virology ,Murine leukemia virus ,medicine ,Animals ,Cells, Cultured ,Enzyme Precursors ,Leukemia, Experimental ,biology ,Caspase 3 ,Flow Cytometry ,biology.organism_classification ,Molecular biology ,Tumor Virus Infections ,Caspases ,Insect Science ,biology.protein ,Pathogenesis and Immunity ,DNA fragmentation ,Poly(ADP-ribose) Polymerases ,Carcinogenesis ,CD8 ,Retroviridae Infections - Abstract
In a previous study we identified the subpopulations of thymus cells that were infected by the lymphomagenic MCF13 murine leukemia virus (MLV) (F. K. Yoshimura, T. Wang, and M. Cankovic, J. Virol. 73:4890–4898, 1999) and observed an effect on thymus size by virus infection. In this report we describe our results which demonstrate that MCF13 MLV infection of thymuses reduced the number of T lymphocytes in this organ. Histological examination showed diffuse lymphocyte depletion, which was most striking in the CD4+CD8+lymphocyte-enriched cortical zone. Consistent with this, flow cytometric analysis showed that the lymphocytes which were depleted were predominantly the immature CD3−CD4+CD8+and CD3+CD4+CD8+cells. A comparison of the percentages of live, apoptotic, and dead cells of the gp70+and gp70−thymic lymphocytes suggested that this effect on thymus cellularity is a result of virus infection. Studies of the survival of thymic T lymphocytes in culture showed that cells from MCF13 MLV-inoculated mice underwent greater apoptosis and death than cells from control animals. Assays for apoptosis included 7-amino-actinomycin D staining, DNA fragmentation, and cleavage of caspase-3 and poly(ADP-ribose) polymerase proenzymes. Our results suggest that apoptosis of thymic lymphocytes by virus infection is an important step in the early stages of MCF13 MLV tumorigenesis.
- Published
- 2000
17. Genetic and phenotypic characterization of GII-4 noroviruses that circulated during 1987 to 2008
- Author
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Pengwei Huang, Bonita E. Lee, Weiming Zhong, Jarek Meller, Xiao Li Pang, Yang Yang, Tao Wang, Xi Jiang, Ming Tan, and Ming Xia
- Subjects
Canada ,Genotype ,viruses ,Immunology ,Oligosaccharides ,Sequence Homology ,Virus Attachment ,Sequence alignment ,Biology ,medicine.disease_cause ,Antibodies, Viral ,Microbiology ,Evolution, Molecular ,Mice ,fluids and secretions ,Antigen ,Oligosaccharide binding ,Virology ,medicine ,Animals ,Cluster Analysis ,Humans ,Binding site ,Saliva ,Caliciviridae Infections ,Genetics ,Mutation ,Mice, Inbred BALB C ,Norovirus ,Sequence Analysis, DNA ,United States ,Gastroenteritis ,Capsid ,Genetic Diversity and Evolution ,Insect Science ,biology.protein ,Blood Group Antigens ,RNA, Viral ,Antibody - Abstract
The predominance and continual emergence of new variants in GII-4 noroviruses (NVs) in recent years have raised questions about the role of host immunity and histo-blood group antigens (HBGAs) in NV evolution. To address these questions, we performed a genetic and phenotypic characterization of GII-4 variants circulating in the past decade (1998 to 2008). Ninety-three GII-4 sequences were analyzed, and of them, 16 strains representing 6 genetic clusters were selected for further characterization. The HBGA binding properties were determined by both saliva- and oligosaccharide-binding assays using P particles as a model of NV capsid. The antigenic properties were also examined by enzyme immunoassay (EIA), Western blot analysis, and receptor blocking assay, using P-particle-specific antibodies from immunized mice and GII-4 virus-infected patients. Our results showed that 15 of the 16 GII-4 viruses bound to saliva of all A, B, and O secretors. Oligosaccharide binding assays yielded largely consistent results, although the binding affinities to some oligosaccharides varied among some strains. The only nonbinder had a mutation in the binding site. While antigenic variations were detected among the 16 strains, significant cross-blocking on the HBGA binding was also noted. Sequence alignment revealed high conservation of HBGA binding interfaces with some variations in adjacent regions. Taken together, our data suggested that the ability of GII-4 to recognize different secretor HBGAs persisted over the past decade, which may explain the predominance of GII-4 over other genotypes. Our data also indicated that both the host immunity and HBGAs play a role in NV evolution. While host immunity may continue driving NV for antigenic change, the functional selection by the HBGAs tends to lock the architecture of the capsid/HBGA interfaces and allows only limited variations outside the HBGA binding sites. A potential outcome of such counterselection between theses two factors in NV evolution is discussed.
- Published
- 2010
18. A single amino acid difference in human APOBEC3H variants determines HIV-1 Vif sensitivity
- Author
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Ke Zhao, Anjie Zhen, Tao Wang, Yong Xiong, and Xiao Fang Yu
- Subjects
Models, Molecular ,Proteasome Endopeptidase Complex ,viruses ,Immunology ,Mutant ,Molecular Sequence Data ,Transfection ,Microbiology ,Cell Line ,Cytosine Deaminase ,chemistry.chemical_compound ,Aminohydrolases ,Virology ,MG132 ,medicine ,vif Gene Products, Human Immunodeficiency Virus ,Humans ,Amino Acid Sequence ,APOBEC3G ,Peptide sequence ,Genetics ,chemistry.chemical_classification ,Genes, vif ,biology ,Base Sequence ,Sequence Homology, Amino Acid ,virus diseases ,Genetic Variation ,biochemical phenomena, metabolism, and nutrition ,Recombinant Proteins ,Ubiquitin ligase ,Amino acid ,Protein Structure, Tertiary ,chemistry ,Amino Acid Substitution ,Haplotypes ,Genetic Diversity and Evolution ,Insect Science ,Host-Pathogen Interactions ,biology.protein ,Proteasome inhibitor ,HIV-1 ,CUL5 ,medicine.drug ,Plasmids - Abstract
Several variants of APOBEC3H (A3H) have been identified in different human populations. Certain variants of this protein are particularly potent inhibitors of retrotransposons and retroviruses, including HIV-1. However, it is not clear whether HIV-1 Vif can recognize and suppress the antiviral activity of A3H variants, as it does with other APOBEC3 proteins. We now report that A3H_Haplotype II (HapII), a potent inhibitor of HIV-1 in the absence of Vif, can indeed be degraded by HIV-1 Vif. Vif-induced degradation of A3H_HapII was blocked by the proteasome inhibitor MG132 and a Cullin5 (Cul5) dominant negative mutant. In addition, Vif mutants that were incapable of assembly with the host E3 ligase complex factors Cul5, ElonginB, and ElonginC were also defective for A3H_HapII suppression. Although we found that Vif hijacks the same E3 ligase to degrade A3H_HapII as it does to inactivate APOBEC3G (A3G) and APOBEC3F (A3F), more Vif motifs were involved in A3H_HapII inactivation than in either A3G or A3F suppression. In contrast to A3H_HapII, A3H_Haplotype I (HapI), which differs in only three amino acids from A3H_HapII, was resistant to HIV-1 Vif-mediated degradation. We also found that residue 121 was critical for determining A3H sensitivity and binding to HIV-1 Vif.
- Published
- 2009
19. A patch of positively charged amino acids surrounding the human immunodeficiency virus type 1 Vif SLVx4Yx9Y motif influences its interaction with APOBEC3G
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Zhiwen He, Xiao Fang Yu, Tao Wang, Rongzhen Xu, and Gongying Chen
- Subjects
viruses ,Immunology ,Molecular Sequence Data ,APOBEC-3G Deaminase ,Plasma protein binding ,Biology ,Microbiology ,Cell Line ,Cytosine Deaminase ,Virology ,Cytidine Deaminase ,Protein Interaction Mapping ,vif Gene Products, Human Immunodeficiency Virus ,Humans ,Protein Interaction Domains and Motifs ,Amino Acid Sequence ,Structural motif ,Peptide sequence ,APOBEC3G ,chemistry.chemical_classification ,virus diseases ,biochemical phenomena, metabolism, and nutrition ,Amino acid ,Cell biology ,Biochemistry ,chemistry ,Amino Acid Substitution ,Insect Science ,HIV-1 ,Mutagenesis, Site-Directed ,Pathogenesis and Immunity ,Protein folding ,CUL5 ,Protein Binding - Abstract
The amino-terminal region of the Vif molecule in human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus (SIV) contains a conserved SLV/Ix4Yx9Y motif that was first described in 1992, but the importance of this motif for Vif function has not yet been examined. Our characterization of the amino acids surrounding this motif in HIV-1 Vif indicated that the region is critical for APOBEC3 suppression. In particular, amino acids K22, K26, Y30, and Y40 were found to be important for the Vif-induced degradation and suppression of cellular APOBEC3G (A3G). However, mutation of these residues had little effect on the Vif-mediated suppression of A3F, A3C, or A3DE, suggesting that these four residues are not important for Vif assembly with the Cul5 E3 ubiquitin ligase or protein folding in general. The LV portion of the Vif SLV/Ix4Yx9Y motif was found to be required for optimal suppression of A3F, A3C, or A3DE. Thus, the SLV/Ix4Yx9Y motif and surrounding amino acids represent an important functional domain in the Vif-mediated defense against APOBEC3. In particular, the positively charged K26 of HIV-1 Vif is invariably conserved within the SLV/Ix4Yx9Y motif of HIV/SIV Vif molecules and was the most critical residue for A3G inactivation. A patch of positively charged and hydrophilic residues (K 22 x 3 K 26 x 3 Y 30 x 9 YRHHY 44 ) and a cluster of hydrophobic residues (V 55 xIPLx 4-5 LxΦx2YWxL 72 ) were both involved in A3G binding and inactivation. These structural motifs in HIV-1 Vif represent attractive targets for the development of lead inhibitors to combat HIV infection.
- Published
- 2009
20. Molecularly cloned SHIV-1157ipd3N4: a highly replication- competent, mucosally transmissible R5 simian-human immunodeficiency virus encoding HIV clade C Env
- Author
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Helena Ong, C. M. McCann, Elizabeth Strobert, Weidong Xu, James G. Else, Robert A. Rasmussen, E. Shai-Kobiler, L. M. Goins, Ricky D. Grisson, Saied Mirshahidi, W. E. Secor, Harold M. McClure, Charles E. Wood, Claudia R. Ruprecht, Agnès-Laurence Chenine, P.-L. Li, Hong Zhang, James B. Whitney, Chipeppo Kankasa, Ruijiang Song, Tao Wang, and Ruth M. Ruprecht
- Subjects
Receptors, CXCR5 ,viruses ,Immunology ,Molecular Sequence Data ,Simian Acquired Immunodeficiency Syndrome ,HIV Infections ,Biology ,medicine.disease_cause ,Recombinant virus ,Virus Replication ,Microbiology ,Peripheral blood mononuclear cell ,Virus ,Serial passage ,Administration, Rectal ,Virology ,medicine ,Animals ,Humans ,Amino Acid Sequence ,Cloning, Molecular ,Receptors, Cytokine ,Chimera ,virus diseases ,Gene Products, env ,Infant ,Simian immunodeficiency virus ,AIDS Vaccines ,biology.organism_classification ,Macaca mulatta ,Long terminal repeat ,Insect Science ,Lentivirus ,HIV-1 ,Pathogenesis and Immunity ,Receptors, Chemokine ,Simian Immunodeficiency Virus - Abstract
Human immunodeficiency virus type 1 (HIV-1) clade C causes >50% of all HIV infections worldwide, and an estimated 90% of all transmissions occur mucosally with R5 strains. A pathogenic R5 simian-human immunodeficiency virus (SHIV) encoding HIV clade Cenvis highly desirable to evaluate candidate AIDS vaccines in nonhuman primates. To this end, we generated SHIV-1157i, a molecular clone from a Zambian infant isolate that carries HIV clade Cenv. SHIV-1157i was adapted by serial passage in five monkeys, three of which developed peripheral CD4+T-cell depletion. After the first inoculated monkey developed AIDS at week 137 postinoculation, transfer of its infected blood to a naïve animal induced memory T-cell depletion and thrombocytopenia within 3 months in the recipient. In parallel, genomic DNA from the blood donor was amplified to generate the late proviral clone SHIV-1157ipd3. To increase the replicative capacity of SHIV-1157ipd3, an extra NF-κB binding site was engineered into its 3′ long terminal repeat, giving rise to SHIV-1157ipd3N4. This virus was exclusively R5 tropic and replicated more potently in rhesus peripheral blood mononuclear cells than SHIV-1157ipd3 in the presence of tumor necrosis factor alpha. Rhesus macaques of Indian and Chinese origin were next inoculated intrarectally with SHIV-1157ipd3N4; this virus replicated vigorously in both sets of monkeys. We conclude that SHIV-1157ipd3N4 is a highly replication-competent, mucosally transmissible R5 SHIV that represents a valuable tool to test candidate AIDS vaccines targeting HIV-1 clade C Env.
- Published
- 2006
21. Sequences between the enhancer and promoter in the long terminal repeat affect murine leukemia virus pathogenicity and replication in the thymus
- Author
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Milena Cankovic, Tao Wang, and Fayth K. Yoshimura
- Subjects
viruses ,Immunology ,Mutant ,Viral transformation ,Thymus Gland ,Biology ,Virus Replication ,Microbiology ,Virus ,Mice ,Mice, Inbred AKR ,Virology ,Murine leukemia virus ,Animals ,Enhancer ,Promoter Regions, Genetic ,Thymic Lymphoma ,NF-kappa B ,Terminal Repeat Sequences ,Thymus Neoplasms ,biology.organism_classification ,Long terminal repeat ,Lymphocyte Subsets ,Leukemia Virus, Murine ,Enhancer Elements, Genetic ,Viral replication ,Insect Science ,Pathogenesis and Immunity - Abstract
We previously showed that the 93-bp region between the enhancer and promoter (named DEN for downstream of enhancer) of the long terminal repeat (LTR) of the MCF13 murine leukemia virus is an important determinant of the ability of this virus to induce thymic lymphoma. In this study we observed that DEN plays a role in the regulation of virus replication in the thymus during the preleukemic period. A NF-κB site in the DEN region partially contributes to the effect of DEN on both lymphomagenicity and virus replication. To further study the effects of DEN and the NF-κB site on viral pathogenicity during the preleukemic period, we examined replication of wild-type and mutant viruses with a deletion of the NF-κB site or the entire DEN region in the thymus. Thymic lymphocytes which were infected with wild-type and mutant viruses were predominantly the CD3 − CD4 + CD8 + and CD3 + CD4 + CD8 + cells. The increase in infection by wild-type virus and both mutant viruses of these two subpopulations during the preleukemic period ranged from 9- to 84-fold, depending upon the time point and virus. The major difference between the wild-type and both mutant viruses was the lower rate and lower level of mutant virus replication in these thymic subpopulations. Significant differences in replication between wild-type and both mutant viruses were seen in the CD3 − CD4 + CD8 + and CD3 − CD4 − CD8 − subpopulations, suggesting that these thymic cell types are important targets for viral transformation.
- Published
- 1999
22. Interaction between the SFTSV envelope glycoprotein Gn and STING inhibits the formation of the STING-TBK1 complex and suppresses the NF-κB signaling pathway.
- Author
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Yupei Jia, Feifei Li, Zixiang Liu, Sihua Liu, Mengqian Huang, Xiaoning Gao, Xin Su, Zhiyun Wang, and Tao Wang
- Subjects
- *
INTERFERONS , *TYPE I interferons , *CELLULAR signal transduction , *VIRAL envelope proteins , *INTERFERON regulatory factors , *MITOCHONDRIAL DNA , *VIRUS diseases - Abstract
Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne bunyavirus with high pathogenicity. There has been a gradual increase in the number of reported cases in recent years, with high morbidity and mortality rates. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway plays an important role in the innate immune defense activated by viral infection; however, the role of the cGAS-STING signaling pathway during SFTSV infection is still unclear. In this study, we investigated the relationship between SFTSV infection and cGAS-STING signaling. We found that SFTSV infection caused the release of mitochondrial DNA into the cytoplasm and inhibits downstream innate immune signaling pathways by activating the cytoplasmic DNA receptor cGAS. We found that the SFTSV envelope glycoprotein Gn was a potent inhibitor of the cGAS-STING pathway and blocked the nuclear accumulation of interferon regulatory factor 3 and p65 to inhibit downstream innate immune signaling. Gn of SFTSV interacted with STING to inhibit STING dimerization and inhibited K27-ubiquitin modification of STING to disrupt the assembly of the STING-TANK-binding kinase 1 complex and downstream signaling. In addition, Gn was found to be involved in inducing STING degradation, further inhibiting the downstream immune response. In conclusion, this study identified the important role of the glycoprotein Gn in the antiviral innate immune response and revealed a novel mechanism of immune escape for SFTSV. Moreover, this study increases the understanding of the pathogenic mechanism of SFTSV and provides new insights for further treatment of SFTS. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
23. Nonsegmented Negative-Sense RNA Viruses Utilize N6-Methyladenosine (m6A) as a Common Strategy To Evade Host Innate Immunity.
- Author
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Mijia Lu, Miaoge Xue, Hai-Tao Wang, Kairis, Elizabeth L., Ahmad, Sadeem, Jiangbo Wei, Zijie Zhang, Qinzhe Liu, Yuexiu Zhang, Youling Gao, Garcin, Dominique, Peeples, Mark E., Sharma, Amit, Sun Hur, Chuan He, and Jianrong Li
- Subjects
- *
NATURAL immunity , *TYPE I interferons , *RNA viruses , *RNA methylation , *RNA modification & restriction , *PENTRAXINS , *CARRIER proteins - Abstract
N6-Methyladenosine (m6A) is the most abundant internal RNA modification catalyzed by host RNA methyltransferases. As obligate intracellular parasites, many viruses acquire m6A methylation in their RNAs. However, the biological functions of viral m6A methylation are poorly understood. Here, we found that viral m6A methylation serves as a molecular marker for host innate immunity to discriminate self from nonself RNA and that this novel biological function of viral m6A methylation is universally conserved in several families in nonsegmented negative-sense (NNS) RNA viruses. Using m6A methyltransferase (METTL3) knockout cells, we produced m6A-deficient virion RNAs from the representative members of the families Pneumoviridae, Paramyxoviridae, and Rhabdoviridae and found that these m6A-deficient viral RNAs triggered significantly higher levels of type I interferon compared to the m6A-sufficient viral RNAs, in a RIG-I-dependent manner. Reconstitution of the RIG-I pathway revealed that m6A-deficient virion RNA induced higher expression of RIG-I, bound to RIG-I more efficiently, enhanced RIG-I ubiquitination, and facilitated RIG-I conformational rearrangement and oligomerization. Furthermore, the m6A binding protein YTHDF2 is essential for suppression of the type I interferon signaling pathway, including by virion RNA. Collectively, our results suggest that several families in NNS RNA viruses acquire m6A in viral RNA as a common strategy to evade host innate immunity. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
24. A Single Amino Acid Difference in Human APOBEC3H Variants Determines HIV-1 Vif Sensitivity.
- Author
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Zhen, Anjie, Tao Wang, Ke Zhao, Yong Xiong, and Xiao-Fang Yu
- Subjects
- *
AMINO acids , *RETROVIRUSES , *HIV , *VIRUS inhibitors , *PROTEINS , *LIGASES - Abstract
Several variants of APOBEC3H (A3H) have been identified in different human populations. Certain variants of this protein are particularly potent inhibitors of retrotransposons and retroviruses, including HIV-1. However, it is not clear whether HIV-1 Vif can recognize and suppress the antiviral activity of A3H variants, as it does with other APOBEC3 proteins. We now report that A3H_Haplotype II (HapII), a potent inhibitor of HIV-1 in the absence of Vif, can indeed be degraded by HIV-1 Vif. Vif-induced degradation of A3H_HapII was blocked by the proteasome inhibitor MG132 and a Cullin5 (Cul5) dominant negative mutant. In addition, Vif mutants that were incapable of assembly with the host E3 ligase complex factors Cul5, ElonginB, and ElonginC were also defective for A3H_HapII suppression. Although we found that Vif hijacks the same E3 ligase to degrade A3H_HapII as it does to inactivate APOBEC3G (A3G) and APOBEC3F (A3F), more Vif motifs were involved in A3H_HapII inactivation than in either A3G or A3F suppression. In contrast to A3H_HapII, A3H_Haplotype I (HapI), which differs in only three amino acids from A3H_HapII, was resistant to HIV-1 Vif-mediated degradation. We also found that residue 121 was critical for determining A3H sensitivity and binding to HIV-1 Vif. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
25. 7SL RNA Mediates Virion Packaging of the Antiviral Cytidine Deaminase APOBEC3G.
- Author
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Tao Wang, Chunjuan Tian, Wenyan Zhang, Kun Luo, Sarkis, Phuong Thi Nguyen, Lillian Yu, Bindong Liu, Yunkai Yu, and Xiao-Fang Yu
- Subjects
- *
RNA , *ADENOSINE deaminase , *ANTIVIRAL agents , *RETROVIRUS diseases , *RNA polymerases , *MESSENGER RNA , *TRANSFER RNA , *PREVENTION - Abstract
Cytidine deaminase APOBEC3G (A3G) has broad antiviral activity against diverse retroviruses and/or retrotransposons, and its antiviral functions are believed to rely on its encapsidation into virions in an RNA-dependent fashion. However, the cofactors of A3G virion packaging have not yet been identified. We demonstrate here that A3G selectively interacts with certain polymerase III (Pol III)-derived RNAs, including Y3 and 7SL RNAs. Among A3G-binding Pol III-derived RNAs, 7SL RNA was preferentially packaged into human immunodeficiency virus type 1 (HIV-1) particles. Efficient packaging of 7SL RNA, as well as A3G, was mediated by the RNA-binding nucleocapsid domain of HIV-1 Gag. A3G mutants that had reduced 7SL RNA binding but maintained wild-type levels of mRNA and tRNA binding were packaged poorly and had impaired antiviral activity. Reducing 7SL RNA packaging by overexpression of SRP19 proteins inhibited 7SL RNA and A3G virion packaging and impaired its antiviral function. Thus, 7SL RNA that is encapsidated into diverse retroviruses is a key cofactor of the antiviral A3G. This selective interaction of A3G with certain Pol III-derived RNAs raises the question of whether A3G and its cofactors may have as-yet-unidentified cellular functions. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
26. Cytidine Deaminases APOBEC3G and APOBEC3F Interact with Human Immunodeficiency Virus Type 1 Integrase and Inhibit Proviral DNA Formation.
- Author
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Kun Luo, Tao Wang, Bindong Liu, Chunjuan Tian, Zuoxiang Xiao, Kappes, John, and Xiao-Fang Yu
- Subjects
- *
DNA , *HIV , *VIRAL replication , *GENETIC transcription , *DEAMINATION - Abstract
APOBEC3G (A3G) is a single-stranded DNA cytidine deaminase that targets retroviral minus-strand DNA and has potent antiviral activity against diverse retroviruses. However, the mechanisms of A3G antiviral functions are incompletely understood. Here we demonstrate that A3G, A3F, and, to a lesser extent, the noncatalytic A3GC291S block human immunodeficiency virus type 1 (HIV-1) replication by interfering with proviral DNA formation. In HIV-1 virions, A3G interacted with HIV-1 integrase and nucleocapsid, key viral factors for reverse transcription and integration. Unlike A3G, the weak antiviral A3C cytidine deaminase did not interact with either of these factors and did not affect viral reverse transcription or proviral DNA formation. Thus, multiple steps of the HIV-1 replication cycle, most noticeably the formation of proviral DNA, are inhibited by both cytidine deamination-dependent and -independent mechanisms. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
27. The H240R Protein of African Swine Fever Virus Inhibits Interleukin 1β Production by Inhibiting NEMO Expression and NLRP3 Oligomerization.
- Author
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Pingping Zhou, Jingwen Dai, Kehui Zhang, Tao Wang, Lian-Feng Li, Yuzi Luo, Yuan Sun, Hua-Ji Qiu, and Su Li
- Subjects
- *
AFRICAN swine fever virus , *AFRICAN swine fever , *CLASSICAL swine fever , *NLRP3 protein , *OLIGOMERIZATION , *ALVEOLAR macrophages , *PLANT viruses - Abstract
The H240R protein (pH240R), encoded by the H240R gene of African swine fever virus (ASFV), is a 241-amino-acid capsid protein. We previously showed that the deletion of H240R from the ASFV genome, creating ASFV-ΔH240R, resulted in an approximately 2-log decrease in infectious virus production compared with the wild-type ASFV strain (ASFV-WT), and ASFV-ΔH240R induced higher interleukin 1β (IL-1β) production in porcine alveolar macrophages (PAMs) than did ASFV-WT, but the underlying mechanism remains to be elucidated. Here, we demonstrate that the activation of the NF-κB signaling and NLRP3 inflammasome was markedly induced in PAMs upon ASFV-ΔH240R infection compared with ASFV-WT. Moreover, pH240R inhibited NF-κB activation by interacting with NEMO and promoting the autophagymediated lysosomal degradation of NEMO, resulting in reduced pro-IL-1β transcription. Strikingly, NLRP3 deficiency in PAMs inhibited the ASFV-DH240R-induced IL-1β secretion and caspase 1 activation, indicating an essential role of NLRP3 inflammasome activation during ASFV-ΔH240R replication. Mechanistically, pH240R interacted with NLRP3 to inhibit its oligomerization, leading to decreased IL-1β production. Furthermore, the inhibition of the NF-κB signaling and NLRP3 inflammasome activation promoted ASFV-ΔH240R replication in PAMs. Taken together, the results of this study reveal an antagonistic mechanism by which pH240R suppresses the host immune response by manipulating activation of the NF-κB signaling and NLRP3 inflammasome, which might guide the rational design of live attenuated vaccines or therapeutic strategies against ASF in the future. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
28. Dabie bandavirus Nonstructural Protein Interacts with Actin to Induce F-Actin Rearrangement and Inhibit Viral Adsorption and Entry.
- Author
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Hongyun Liu, Sihua Liu, Zixiang Liu, Xiaoning Gao, Leling Xu, Mengqian Huang, Yazhi Su, Zhiyun Wang, and Tao Wang
- Subjects
- *
CYTOSKELETON , *F-actin , *ACTIN , *CELL aggregation , *CLATHRIN , *ENDOCYTOSIS , *CELLULAR inclusions , *UBIQUITINATION - Abstract
Dabie bandavirus (DBV) is an emerging Bandavirus that causes multiorgan failure with a high fatality rate in humans. While many viruses can manipulate the actin cytoskeleton to facilitate viral growth, the regulation pattern of the actin cytoskeleton and the molecular mechanisms involved in DBV entry into the host cells remain unclear. In this study, we demonstrate that expression of nonstructural protein (NSs) or infection with DBV induces actin rearrangement, which presents a point-like distribution, and this destruction is dependent on inclusion bodies (IBs). Further experiments showed that NSs inhibits viral adsorption by destroying the filopodium structure. In addition, NSs also compromised the viral entry by inhibiting clathrin aggregation on the cell surface and capturing clathrin into IBs. Furthermore, NSs induced clathrin light chain B (CLTB) degradation through the K48-linked ubiquitin proteasome pathway, which could negatively regulate clathrin-mediated endocytosis, inhibiting the viral entry. Finally, we confirmed that this NSs-induced antiviral mechanism is broadly applicable to other viruses, such as enterovirus 71 (EV71) and influenza virus, A/PR8/34 (PR8), which use the same clathrin-mediated endocytosis to enter host cells. In conclusion, our study provides new insights into the role of NSs in inhibiting endocytosis and a novel strategy for treating DBV infections. IMPORTANCE Dabie bandavirus (DBV), a member of the Phenuiviridae family, is a newly emerging tick-borne pathogen that causes multifunctional organ failure and even death in humans. The actin cytoskeleton is involved in various crucial cellular processes and plays an important role in viral life activities. However, the relationship between DBV infection and the actin cytoskeleton has not been described in detail. Here, we show for the first time the interaction between NSs and actin to induce actin rearrangement, which inhibits the viral adsorption and entry. We also identify a key mechanism underlying NSs-induced entry inhibition in which NSs prevents clathrin aggregation on the cell surface by hijacking clathrin into the inclusion body and induces CLTB degradation through the K48-linked ubiquitination modification. This paper is the first to reveal the antiviral mechanism of NSs and provides a theoretical basis for the search for new antiviral targets. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
29. Deletion of the H240R Gene of African Swine Fever Virus Decreases Infectious Progeny Virus Production Due to Aberrant Virion Morphogenesis and Enhances Inflammatory Cytokine Expression in Porcine Macrophages.
- Author
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Pingping Zhou, Lian-Feng Li, Kehui Zhang, Bing Wang, Lijie Tang, Miao Li, Tao Wang, Yuan Sun, Su Li, and Hua-Ji Qiua
- Subjects
- *
AFRICAN swine fever virus , *AFRICAN swine fever , *PRIONS , *CYTOSKELETAL proteins , *VIRION , *DELETION mutation - Abstract
African swine fever virus (ASFV) is a complex nucleocytoplasmic large DNA virus that causes African swine fever, a lethal hemorrhagic disease that currently threatens the pig industry. Recent studies have identified the viral structural proteins of infectious ASFV particles. However, the functional roles of several ASFV structural proteins remain largely unknown. Here, we characterized the function of the ASFV structural protein H240R (pH240R) in virus morphogenesis. pH240R was identified as a capsid protein by using immunoelectron microscopy and interacted with the major capsid protein p72 by pulldown assays. Using a recombinant ASFV, ASFV-DH240R, with the H240R gene deleted from the wild-type ASFV (ASFV-WT) genome, we revealed that the infectious progeny virus titers were reduced by approximately 2.0 logs compared with those of ASFV-WT. Furthermore, we demonstrated that the growth defect was due to the generation of noninfectious particles with a higher particle-to-infectious titer ratio in ASFV-DH240R-infected primary porcine alveolar macrophages (PAMs) than in those infected with ASFV-WT. Importantly, we found that pH240R did not affect virus-cell binding, endocytosis, or egress but did affect ASFV assembly; noninfectious virions containing large aberrant tubular and bilobulate structures comprised nearly 98% of all virions observed in ASFV-DH240R-infected PAMs by electron microscopy. Notably, we demonstrated that ASFV-DH240R infection induced high-level expression of inflammatory cytokines in PAMs. Collectively, we show for the first time that pH240R is essential for ASFV icosahedral capsid formation and infectious particle production. Also, these results highlight the importance of pH240R in ASFV morphogenesis and provide a novel target for the development of ASF vaccines and antivirals. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
30. A Patch of Positively Charged Amino Acids Surrounding the Human Immunodeficiency Virus Type 1 Vif SLVx4Yx9Y Motif Influences Its Interaction with APOBEC3G.
- Author
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Gongying Chen, Zhiwen He, Tao Wang, Rongzhen Xu, and Xiao-Fang Yu
- Subjects
- *
HIV , *HIV infections , *AMINO acids , *SIMIAN viruses , *UBIQUITIN , *IMMUNODEFICIENCY , *IMMUNOSUPPRESSION - Abstract
The amino-terminal region of the Vif molecule in human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus (SIV) contains a conserved SLV/Ix4Yx9Y motif that was first described in 1992, but the importance of this motif for Vif function has not yet been examined. Our characterization of the amino acids surrounding this motif in HIV-1 Vif indicated that the region is critical for APOBEC3 suppression. In particular, amino acids K22, K26, Y30, and Y40 were found to be important for the Vif-induced degradation and suppression of cellular APOBEC3G (A3G). However, mutation of these residues had little effect on the Vif-mediated suppression of A3F, A3C, or A3DE, suggesting that these four residues are not important for Vif assembly with the Cul5 E3 ubiquitin ligase or protein folding in general. The LV portion of the Vif SLV/Ix4Yx9Y motif was found to be required for optimal suppression of A3F, A3C, or A3DE. Thus, the SLV/Ix4Yx9Y motif and surrounding amino acids represent an important functional domain in the Vif-mediated defense against APOBEC3. In particular, the positively charged K26 of HIV-1 Vif is invariably conserved within the SLV/Ix4Yx9Y motif of HIV/SIV Vif molecules and was the most critical residue for A3G inactivation. A patch of positively charged and hydrophilic residues (K22x3K26x3Y30x9YRHHY44) and a cluster of hydrophobic residues (V55xIPLx4-5LxΦ2YWxL72) were both involved in A3G binding and inactivation. These structural motifs in HIV-1 Vif represent attractive targets for the development of lead inhibitors to combat HIV infection. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
31. Orsay CP-δ adopts a novel β-bracelet structural fold and incorporates into virions as a head fiber.
- Author
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Guo, Yusong R., Fan, Yanlin, Ying Zhou, Miao Jin, Zhang, Jim L., Jiang, Hongbing, Holt, Matthew V., Tao Wang, Young, Nicolas L., Wang, David, Weiwei Zhong, and Tao, Yizhi J.
- Subjects
- *
CELL receptors , *VIRION , *CHIMERIC proteins , *VIRUS diseases , *CAENORHABDITIS elegans , *NON-coding RNA , *CAENORHABDITIS - Abstract
Fiber proteins are commonly found in eukaryotic and prokaryotic viruses where they play important roles in mediating viral attachment and host cell entry. They typically form trimeric structures and are incorporated into virions via non-covalent interactions. The small RNA virus Orsay, which specifically infects the laboratory model Caenorhabditis elegans, encodes a fibrous protein d that can be expressed as a free protein and as a capsid protein-d (CP-d) fusion protein. Free d has previously been demonstrated to facilitate viral exit following intracellular expression; however, the biological significance and prevalence of CP-d remained relatively unknown. Here, we demonstrate that Orsay CP-d is covalently incorporated into infectious particles, the first example of any attached viral fibers known to date. The crystal structure of d(1-101) (i.e. a deletion mutant containing the first 101 amino acid (aa) residues of d) reveals a pentameric, 145-Å long fiber with an N-terminal coiled coil followed by multiple ß-bracelet repeats. Electron micrographs of infectious virions depict particle-associated CP-d fibers with dimensions similar to free d. d proteins from two other nematode viruses Le Blanc and Santeuil, which both specifically infect Caenorhabditis briggsae, were also found to form fibrous molecules. Recombinant Le Blanc d was able to block Orsay virus infection in worm culture and vice versa, suggesting these two viruses likely compete for the same cell receptor(s). Thus, we propose that while CP-d likely mediates host cell attachment for all three nematode viruses, additional downstream factor(s) ultimately determine the host specificity and range of each virus. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
32. Binding of Duck Tembusu virus nonstructural protein 2A to duSTING disrupts the induction of its signal transduction cascade to inhibit IFN-β induction.
- Author
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Wei Zhang, Bowen Jiang, Miao Zeng, Yanping Duan, Zhen Wu, Yuanyuan Wu, Tao Wang, Mingshu Wang, Renyong Jia, Dekang Zhu, Mafeng Liu, Xinxin Zhao, Qiao Yang, Ying Wu, Shaqiu Zhang, Yunya Liu, Ling Zhang, Yanling Yu, Leichang Pan, and Shun Chen
- Subjects
- *
VIRAL nonstructural proteins , *VIRAL proteins , *CELLULAR signal transduction , *DUCK plague , *TYPE I interferons , *INTERFERONS - Abstract
Duck Tembusu virus (DTMUV), which is similar to other mosquito-borne flaviviruses that replicate well in most mammalian cells, is an emerging pathogenic flavivirus that has caused epidemics in egg-laying and breeding waterfowl. Immune organ defects and neurological dysfunction are the main clinical symptoms of DTMUV infection. Preinfection with DTMUV makes the virus impervious to later interferon (IFN) treatment, revealing that DTMUV has evolved some strategies to defend against host IFN-dependent antiviral responses. Immune inhibition was further confirmed by screening for DTMUV-encoded proteins, which suggested that NS2A significantly inhibited IFN-β and IFN-stimulated response element (ISRE) promoter activity in a dose-dependent manner and facilitated reinfection with duck plague virus (DPV). DTMUV NS2A was able to inhibit duck RIG-I-, MDA5-, MAVS-, STING and TBK1- induced IFN-β transcription, but not duck TBK1- and IRF7-mediated effective phases of IFN response. Furthermore, we found that NS2A competed with duTBK1 in binding to duSTING, impaired duSTING-duSTING binding and reduced duTBK1 phosphorylation, leading to the subsequent inhibition of IFN production. Importantly, we first identified that the W164A, Y167A and S361A mutations in duSTING significantly impaired the NS2A-duSTING interaction, which is important for NS2A-induced IFN-β inhibition. Hence, our data demonstrated that DTMUV NS2A disrupts duSTING-dependent antiviral cellular defenses by binding with duSTING, which provides a novel mechanism by which DTMUV subverts host innate immune responses. The potential interaction sites between NS2A and duSTING may be the targets of future novel antiviral therapies and vaccine development. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
33. Typical Stress Granule proteins interact with the 3'-UTR of Enterovirus D68 to inhibit viral replication.
- Author
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Jinyan Cheng, Shuai Gao, Cheng Zhu, Sihua Liu, Jinyu Li, Jun Kang, Zhiyun Wang, and Tao Wang
- Subjects
- *
HEAT shock proteins , *VIRAL replication , *NEUROLOGICAL disorders , *CYTOTOXIC T cells , *RESPIRATORY diseases - Abstract
Stress granules (SGs) are formed in the cytoplasm under environmental stress, including viral infection. Human enterovirus D68 (EV-D68) is a highly pathogenic virus, which can cause serious respiratory and neurological diseases. At present, there is no effective drug or vaccine against EV-D68 infection, and the relationship between EV-D68 infection and SGs is poorly understood. This study revealed the biological function of SGs in EV-D68 infection. Our results suggest that EV-D68 infection induced the accumulation of SG markers proteins, G3BP1, TIA1, and HUR, in the cytoplasm of infected host cells during early infection but inhibited their accumulation during the late stage. Simultaneously, we revealed that EV-D68 infection induces HUR, TIA1, and G3BP1 co-localization, which marks the formation of typical SGs dependent on PKR and eIF2α phosphorylation. In addition, we found that TIA1, HUR and G3BP1 were capable of targeting the 3'-untranslated regions (UTR) of EV-D68 RNA to inhibit viral replication. However, the formation of SGs in response to arsenite (Ars) gradually decreased as the infection progressed, and G3BP1 was cleaved in the late stage as a strategy to antagonize SGs. Our findings have important implications in understanding the mechanism of interaction between EV-D68 and the host, while providing a potential target for the development of antiviral drugs. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
34. The Severe Fever with Thrombocytopenia Syndrome Virus NSs Protein Interacts with CDK1 To Induce G2 Cell Cycle Arrest and Positively Regulate Viral Replication.
- Author
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Sihua Liu, Hongyun Liu, Jun Kang, Leling Xu, Keke Zhang, Xueping Li, Wen Hou, Zhiyun Wang, and Tao Wang
- Subjects
- *
CELL cycle , *VIRAL proteins , *VIRAL replication , *CYCLIN-dependent kinases , *VIRAL cell cycle , *HEMORRHAGIC fever - Abstract
Severe fever with thrombocytopenia syndrome virus (SFTSV) is a newly identified phlebovirus associated with severe hemorrhagic fever in humans. While many viruses subvert the host cell cycle to promote viral growth, it is unknown whether this is a strategy employed by SFTSV. In this study, we investigated how SFTSV manipulates the cell cycle and the effect of the host cell cycle on SFTSV replication. Our results suggest that cells arrest at the G2/M transition following infection with SFTSV. The accumulation of cells at the G2/M transition did not affect virus adsorption and entry but did facilitate viral replication. In addition, we found that SFTSV NSs, a nonstructural protein that forms viroplasm-like structures in the cytoplasm of infected cells and promotes virulence by modulating the interferon response, induces a large number of cells to arrest at the G2/M transition by interacting with CDK1. The interaction between NSs and CDK1, which is inclusion body dependent, inhibits formation and nuclear import of the cyclin B1-CDK1 complex, thereby leading to cell cycle arrest. Expression of a CDK1 loss-of-function mutant reversed the inhibitive effect of NSs on the cell cycle, suggesting that this protein is a potential antiviral target. Our study provides new insight into the role of a specific viral protein in SFTSV replication, indicating that NSs induces G2/M arrest of SFTSV-infected cells, which promotes viral replication. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
35. Programmed −2/−1 Ribosomal Frameshifting in Simarteriviruses: an Evolutionarily Conserved Mechanism.
- Author
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Yanhua Li, Firth, Andrew E., Brierley, Ian, Yingyun Cai, Napthine, Sawsan, Tao Wang, Xingyu Yan, Kuhn, Jens H., and Ying Fang
- Subjects
- *
HEMORRHAGIC fever , *PORCINE reproductive & respiratory syndrome , *VIRAL proteins , *RIBOSOMES , *VIRAL nonstructural proteins , *VIRUS diseases , *CARRIER proteins , *REVERSE genetics - Abstract
The −2/−1 programmed ribosomal frameshifting (−2/−1 PRF) mechanism in porcine reproductive and respiratory syndrome virus (PRRSV) leads to the translation of two additional viral proteins, nonstructural protein 2TF (nsp2TF) and nsp2N. This −2/−1 PRF mechanism is transactivated by a viral protein, nsp1β, and cellular poly(rC) binding proteins (PCBPs). Critical elements for −2/−1 PRF, including a slippery sequence and a downstream C-rich motif, were also identified in 11 simarteriviruses. However, the slippery sequences (XXXUCUCU instead of XXXUUUUU) in seven simarteriviruses can only facilitate −2 PRF to generate nsp2TF. The nsp1β of simian hemorrhagic fever virus (SHFV) was identified as a key factor that transactivates both −2 and −1 PRF, and the universally conserved Tyr111 and Arg114 in nsp1β are essential for this activity. In vitro translation experiments demonstrated the involvement of PCBPs in simarterivirus −2/−1 PRF. Using SHFV reverse genetics, we confirmed critical roles of nsp1β, slippery sequence, and C-rich motif in −2/−1 PRF in SHFV-infected cells. Attenuated virus growth ability was observed in SHFV mutants with impaired expression of nsp2TF and nsp2N. Comparative genomic sequence analysis showed that key elements of −2/−1 PRF are highly conserved in all known arteriviruses except equine arteritis virus (EAV) and wobbly possum disease virus (WPDV). Furthermore, −2/−1 PRF with SHFV PRF signal RNA can be stimulated by heterotypic nsp1βs of all non-EAV arteriviruses tested. Taken together, these data suggest that −2/−1 PRF is an evolutionarily conserved mechanism employed in non-EAV/-WPDV arteriviruses for the expression of additional viral proteins that are important for viral replication. IMPORTANCE Simarteriviruses are a group of arteriviruses infecting nonhuman primates, and a number of new species have been established in recent years. Although these arteriviruses are widely distributed among African nonhuman primates of different species, and some of them cause lethal hemorrhagic fever disease, this group of viruses has been undercharacterized. Since wild nonhuman primates are historically important sources or reservoirs of human pathogens, there is concern that simarteriviruses may be preemergent zoonotic pathogens. Thus, molecular characterization of simarteriviruses is becoming a priority in arterivirology. In this study, we demonstrated that an evolutionarily conserved ribosomal frameshifting mechanism is used by simarteriviruses and other distantly related arteriviruses for the expression of additional viral proteins. This mechanism is unprecedented in eukaryotic systems. Given the crucial role of ribosome function in all living systems, the potential impact of the in-depth characterization of this novel mechanism reaches beyond the field of virology. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
36. Acidity/Alkalinity of Japanese Encephalitis Virus E Protein Residue 138 Alters Neurovirulence in Mice.
- Author
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Xuchen Zheng, Hao Zheng, Wu Tong, Guoxin Li, Tao Wang, Liwei Li, Fei Gao, Tongling Shan, Hai Yu, Yanjun Zhou, Yafeng Qiu, Zhiyong Ma, and Guangzhi Tong
- Subjects
- *
JAPANESE encephalitis viruses , *ACIDITY , *ALKALINITY , *MICROBIAL virulence , *GLYCOPROTEINS , *VIRUS attenuation , *JAPANESE B encephalitis vaccines , *HEPARIN - Abstract
The Japanese encephalitis virus (JEV) envelope (E) protein, as one of mediators of virus entry into host cells, plays a critical role in determining virulence. The Glu-to-Lys mutation of residue 138 in E protein (E138) plays an important role in attenuating JEV vaccine strain SA14-14-2. However, it is not clear how E138 attenuates JEV. Here, we demonstrate that the Glu-to-Arg mutation of E138 also determines the attenuation of JEV strain 10S3. Likewise, for its parent strain (HEN0701), a virulence strain, the mutations of E138 are responsible for virulence alteration. Furthermore, we demonstrated that mutations of alkaline residues in E138 contributed to the attenuation of neurovirulence; in contrast, mutations of acidic residues enhanced the neurovirulence of the strains. Moreover, acidity in residue E47 had a similar effect on neurovirulence. Furthermore, the alkaline E138 residue enhanced susceptibility to heparin inhibition in vitro and limited JEV diffusion in mouse brain. These results suggest that the acidity/alkalinity of the E138 residue plays an important role in neurovirulence determination. IMPORTANCE The E protein is the only glycoprotein in mature JEV, and it plays an important role in viral neurovirulence. E protein mutations attenuate JEV neurovirulence through unclear mechanisms. Here, we discovered that E138 is a predominant determinant of JEV neurovirulence. We demonstrated that the alkalinity/acidity of E138 determines JEV neurovirulence. These data contribute to the characterization of the E protein and the rational development of novel JEV vaccines. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
37. Erratum for Zhou et al., ' Deletion of the H240R Gene of African Swine Fever Virus Decreases Infectious Progeny Virus Production Due to Aberrant Virion Morphogenesis and Enhances Inflammatory Cytokine Expression in Porcine Macrophages'.
- Author
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Pingping Zhou, Lian-Feng Li, Kehui Zhang, Bing Wang, Lijie Tang, Miao Li, Tao Wang, Yuan Sun, Su Li, and Hua-Ji Qiu
- Subjects
- *
AFRICAN swine fever virus , *AFRICAN swine fever , *DELETION mutation , *VIRION , *MORPHOGENESIS , *MACROPHAGES - Published
- 2022
- Full Text
- View/download PDF
38. Structure of Severe Fever with Thrombocytopenia Syndrome Virus Nucleocapsid Protein in Complex with Suramin Reveals Therapeutic Potential.
- Author
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Lianying Jiao, Songying Ouyang, Mifang Liang, Fengfeng Niu, Shaw, Neil, Wei Wu, Wei Ding, Cong Jin, Yao Peng, Yanping Zhu, Fushun Zhang, Tao Wang, Chuan Li, Xiaobing Zuo, Luan, Chi-Hao, Dexin Li, and Liu, Zhi-Jie
- Subjects
- *
THROMBOCYTOPENIA , *FEVER , *NUCLEOCAPSID structure , *SURAMIN , *BUNYAVIRUSES , *VIRAL transmission , *GENETIC transcription , *VIRUSES - Abstract
Severe fever with thrombocytopenia syndrome is an emerging infectious disease caused by a novel bunyavirus (SFTSV). Lack of vaccines and inadequate therapeutic treatments have made the spread of the virus a global concern. Viral nucleocapsid protein (N) is essential for its transcription and replication. Here, we present the crystal structures of N from SFTSV and its homologs from Buenaventura (BUE) and Granada (GRA) viruses. The structures reveal that phleboviral N folds into a compact core domain and an extended N-terminal arm that mediates oligomerization, such as tetramer, pentamer, and hexamer of N assemblies. Structural superimposition indicates that phleboviral N adopts a conserved architecture and uses a similar RNA encapsidation strategy as that of RVFV-N. The RNA binding cavity runs along the inner edge of the ring-like assembly. A triple mutant of SFTSV-N, R64D/K67D/K74D, almost lost its ability to bind RNA in vitro, is deficient in its ability to transcribe and replicate. Structural studies of the mutant reveal that both alterations in quaternary assembly and the charge distribution contribute to the loss of RNA binding. In the screening of inhibitors Suramin was identified to bind phleboviral N specifically. The complex crystal structure of SFTSV-N with Suramin was refined to a 2.30-Å resolution. Suramin was found sitting in the putative RNA binding cavity of SFTSV-N. The inhibitory effect of Suramin on SFTSV replication was confirmed in Vero cells. Therefore, a common Suramin-based therapeutic approach targeting SFTSV-N and its homologs could be developed for containing phleboviral outbreaks. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
39. Genetic and Phenotypic Characterization of GII-4 Noroviruses That Circulated during 1987 to 2008.
- Author
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Yang Yang, Ming Xia52, Ming Tan, Pengwei Huang, Weiming Zhong, Xiao Li Pang, Lee, Bonita E., Meller, Jarek, Tao Wang, and Xi Jiang
- Subjects
- *
IMMUNOGLOBULINS , *BLOOD testing , *BLOOD transfusion , *ENZYME-linked immunosorbent assay , *GENETIC polymorphisms - Abstract
The predominance and continual emergence of new variants in GII-4 noroviruses (NVs) in recent years have raised questions about the role of host immunity and histo-blood group antigens (HBGAs) in NV evolution. To address these questions, we performed a genetic and phenotypic characterization of GII-4 variants circulating in the past decade (1998 to 2008). Ninety-three GII-4 sequences were analyzed, and of them, 16 strains representing 6 genetic clusters were selected for further characterization. The HBGA binding properties were determined by both saliva- and oligosaccharide-binding assays using P particles as a model of NV capsid. The antigenic properties were also examined by enzyme immunoassay (EIA), Western blot analysis, and receptor blocking assay, using P-particle-specific antibodies from immunized mice and GII-4 virus-infected patients. Our results showed that 15 of the 16 GII-4 viruses bound to saliva of all A, B, and O secretors. Oligosaccharide binding assays yielded largely consistent results, although the binding affinities to some oligosaccharides varied among some strains. The only nonbinder had a mutation in the binding site. While antigenic variations were detected among the 16 strains, significant cross-blocking on the HBGA binding was also noted. Sequence alignment revealed high conservation of HBGA binding interfaces with some variations in adjacent regions. Taken together, our data suggested that the ability of GII-4 to recognize different secretor HBGAs persisted over the past decade, which may explain the predominance of GII-4 over other genotypes. Our data also indicated that both the host immunity and HBGAs play a role in NV evolution. While host immunity may continue driving NV for antigenic change, the functional selection by the HBGAs tends to lock the architecture of the capsid/HBGA interfaces and allows only limited variations outside the HBGA binding sites. A potential outcome of such counterselection between theses two factors in NV evolution is discussed. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
40. Biochemical and Genetic Characterization of a Novel Human Immunodeficiency Virus Type 1 Inhibitor That Blocks gp120-CD4 Interactions.
- Author
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Qi Guo, Hsu-Tso Ho, Dicker, Ira, Li Fan, Nannan Zhou, Friborg, Jacques, Tao Wang, McAuliffe, Brian V., Hwei-gene Heidi Wang, Rose, Ronald E., Hua Fang, Scarnati, Helen T., Langley, David R., Meanwell, Nicholas A., Abraham, Ralph, Colonno, Richard J., and Pin-fang Lin
- Subjects
- *
HIV infections , *PROTEIN binding - Abstract
Characterizes the interaction between BMS-378806, a small-molecule HIV type 1, and the HIV-1 envelope by using a combination of biochemical and genetic approaches. Competitive inhibition of gp120-CD4 binding by BMS-378806; Binding affinity of BMS378806 to gp120 protein.
- Published
- 2003
- Full Text
- View/download PDF
41. HC-Pro Protein of Potato Virus Y Can Interact with Three Arabidopsis 20S Proteasome Subunits In Planta.
- Author
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Yongsheng Jin, Dongyuan Ma, Jiangli Dong, Jingchen Jin, Daofeng Li, Changwang Deng, and Tao Wang
- Subjects
- *
PROTEINS , *POTATO virus Y , *ARABIDOPSIS , *PROTEINASES , *YEAST - Abstract
The multifunctional protein helper component proteinase (HC-Pro) is thought to interfere with the activity of the 20S proteasome; however, no sites of interaction have been identified for either protein. Here, we first show that the Potato virus Y (PVY) HC-Pro protein can interact with three Arabidopsis 20S proteasome subunits (PAA, PBB, and PBE), using a yeast two-hybrid system and the bimolecular fluorescence complement assay. In addition, yeast two-hybrid analysis of the interaction between several mutant subunits of the 20S proteasome and PVY HC-Pro confirmed that residues 81 to 140 of PAA, 1 to 80 of PBB, and 160 to 274 of PBE are necessary for binding PAA, PBB, and PBE to PVY HC-Pro, respectively. Deletion mutant analysis of PVY HC-Pro showed that the N terminus (residues 1 to 97) is necessary for its interaction with three Arabidopsis 20S proteasome subunits. The ability of HC-Pro to interact and interfere with the activity of the 20S proteasome may help explain the molecular basis of its multifunctional character. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
42. Differential Inhibition of Long Interspersed Element 1 by APOBEC3 Does Not Correlate with High-Molecular-Mass-Complex Formation or P-Body Association.
- Author
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Niewiadomska, Anna Maria, Chunjuan Tian, Lindi Tan, Tao Wang, Phuong Thi Nguyen Sarkis, and Xiao-Fang Yu
- Subjects
- *
PROTEINS , *RETROVIRUSES , *HIV , *RNA , *DNA , *PROTEIN-protein interactions - Abstract
The human cytidine deaminase APOBEC3G (A3G) and other APOBEC3 proteins exhibit differential inhibitory activities against diverse endogenous retroelements and retroviruses, including Vif-deficient human immunodeficiency virus type 1. The potential inhibitory activity of human APOBEC proteins against long interspersed element 1 (LINE-1) has not been fully evaluated. Here, we demonstrate inhibition of LINE-1 by multiple human APOBEC3 cytidine deaminases, including previously unreported activity for A3DE and A3G. More ancient members of APOBEC, cytidine deaminases AID and APOBEC2, had no detectable activity against LINE-1. A3A, which did not form high-molecular-mass (HMM) complexes and interacted poorly with P bodies, was the most potent inhibitor of LINE-1. A3A specifically recognizes LINE-1 RNA but not the other cellular RNAs tested. However, in the presence of LINE-1, A3A became associated with HMM complexes containing LINE-1 RNA. The ability of A3A to recognize LINE-1 RNA required its catalytic domain and was important for its LINE-1 suppression. Although the mechanism of LINE-1 restriction did not seem to involve DNA editing, A3A inhibited the accumulation of nascent LINE-1 DNA, suggesting interference with LINE-1 reverse transcription and/or integration or intracellular movement of LINE-1 ribonucleoprotein. Thus, association with P bodies or cellular HMM complexes could not predict the potency of APOBEC3 anti-LINE-1 activities. The catalytic domain of APOBEC3 proteins may be important for proper folding and target factors such as RNA or protein interaction in addition to cytidine deamination. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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43. Envelope Conformational Changes Induced by Human Immunodeficiency Virus Type 1 Attachment Inhibitors Prevent CD4 Binding and Downstream Entry Events.
- Author
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Hsu-Tso Ho, Li Fan, Nowicka-Sans, Beata, McAuliffe, Brian, Chang-Ben Li, Yamanaka, Gregory, Nannan Zhou, Hua Fang, Dicker, Ira, Dalterio, Richard, Yi-Fei Gong, Tao Wang, Zhiwei Yin, Ueda, Yasutsugu, Matiskella, John, Kadow, John, Clapham, Paul, Robinson, James, Colonno, Richard, and Pin-Fang Lin
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IMMUNODEFICIENCY , *MOLECULES , *PROTEINS , *IMMUNOGLOBULINS , *BIOMOLECULES - Abstract
BMS-488043 is a small-molecule human immunodeficiency virus type 1 (HIV-1) CD4 attachment inhibitor with demonstrated clinical efficacy. The compound inhibits soluble CD4 (sCD4) binding to the 11 distinct HIV envelope gp120 proteins surveyed. Binding of BMS-488043 and that of sCD4 to gp120 are mutually exclusive, since increased concentrations of one can completely block the binding of the other without affecting the maximal gp120 binding capacity. Similarly, BMS-488043 inhibited virion envelope trimers from binding to sCD4-immunoglobulin G (IgG), with decreasing inhibition as the sCD4-IgG concentration increased, and BMS-488043 blocked the sCD4-induced exposure of the gp41 groove in virions. In both virion binding assays, BMS-488043 was active only when added prior to sCD4. Collectively, these results indicate that obstruction of gp120-sCD4 interactions is the primary inhibition mechanism of this compound and that compound interaction with envelope must precede CD4 binding. By three independent approaches, BMS-488043 was further shown to induce conformational changes within gp120 in both the CD4 and CCR5 binding regions. These changes likely prevent gp120-CD4 interactions and downstream entry events. However, BMS-488043 could only partially inhibit CD4 binding to an HIV variant containing a specific envelope truncation and altered gp120 conformation, despite effectively inhibiting the pseudotyped virus infection. Taken together, BMS-488043 inhibits viral entry primarily through altering the envelope conformation and preventing CD4 binding, and other downstream entry events could also be inhibited as a result of these induced conformational changes. [ABSTRACT FROM AUTHOR]
- Published
- 2006
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44. Differential Requirement for Conserved Tryptophans in Human Immunodeficiency Virus Type 1 Vif for the Selective Suppression of APOBEC3G and APOBEC3F.
- Author
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Chunjuan Tian, Xianghui Yu, Wei Zhang, Tao Wang, Rongzhen Xu, and Xiao-Fang Yu
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HIV , *RETROVIRUSES , *AMINES , *ANTIVIRAL agents , *PEPTIDES , *IMMUNOSUPPRESSION - Abstract
APOBEC3G (A3G) and related cytidine deaminases, such as APOBEC3F (A3F), are potent inhibitors of retroviruses. Formation of infectious human immunodeficiency virus type 1 (HIV-1) requires suppression of multiple cytidine deaminases by Vif. Whether HIV-1 Vif recognizes various APOBEC3 proteins through a common mechanism is unclear. The domains in Vif that mediate APOBEC3 recognitions are also poorly defined. The N-terminal region of HIV-1 Vif is unusually rich in Trp residues, which are highly conserved. In the present study, we examined the role of these Trp residues in the suppression of APOBEC3 proteins by HIV-1 Vif. We found that most of the highly conserved Trp residues were required for efficient suppression of both A3G and A3F, but some of these residues were selectively required for the suppression of A3F but not A3G. Mutant Vif molecules in which Ala was substituted for Trp79 and, to a lesser extent, for Trp11 remained competent for A3G interaction and its suppression; however, they were defective for A3F interaction and therefore could not efficiently suppress the antiviral activity of A3F. Interestingly, while the HIV-1 Vif-mediated degradation of A3G was not affected by the different C-terminal tag peptides, that of A3F was significantly influenced by its C-terminal tags. These data indicate that the mechanisms by which HIV-1 Vif recognizes its target molecules, A3G and A3F, are not identical. The fact that several highly conserved residues in Vif are required for the suppression of A3F but not that of A3G suggests a critical role for A3F in the restriction of HIV-1 in vivo. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
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