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Results: 1 to 10 of 59

Publication Record


Potent Neutralizing Human Monoclonal Antibodies Preferentially Target Mature Dengue Virus Particles: Implication for Novel Strategy for Dengue Vaccine.
Tsai WY, Chen HL, Tsai JJ, Dejnirattisai W, Jumnainsong A, Mongkolsapaya J, Screaton G, Crowe JE, Wang WK
(2018) J Virol 92:
MeSH Terms: Adult, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Dengue, Dengue Vaccines, Dengue Virus, Humans, Viral Envelope Proteins, Virion
Show Abstract · Added March 31, 2019
The four serotypes of dengue virus (DENV) cause the most important mosquito-borne viral disease in humans. The envelope (E) protein is the major target of neutralizing antibodies and contains 3 domains (domain I [DI], DII, and DIII). Recent studies reported that human monoclonal antibodies (MAbs) recognizing DIII, the D1/DII hinge, the E-dimer epitope, or a quaternary epitope involving DI/DII/DIII are more potently neutralizing than those recognizing the fusion loop (FL) of DII. Due to inefficient cleavage of the premembrane protein, DENV suspensions consist of a mixture of mature, immature, and partially immature particles. We investigated the neutralization and binding of 22 human MAbs to DENV serotype 1 (DENV1) virions with differential maturation status. Compared with FL MAbs, DIII, DI/DII hinge, and E-dimer epitope MAbs showed higher maximum binding and avidity to mature particles relative to immature particles; this feature may contribute to the strong neutralizing potency of such MAbs. FL-specific MAbs required 57 to 87% occupancy on mature particles to achieve half-maximal neutralization (NT), whereas the potently neutralizing MAbs achieved NT states at 20 to 38% occupancy. Analysis of the MAb repertoire and polyclonal sera from patients with primary DENV1 infection supports the immunodominance of cross-reactive anti-E antibodies over type-specific antibodies. After depletion with viral particles from a heterologous DENV serotype, the type-specific neutralizing antibodies remained and showed binding features shared by potent neutralizing MAbs. Taken together, these findings suggest that the use of homogeneous mature DENV particles as an immunogen may induce more potent neutralizing antibodies against DENV than the use of immature or mixed particles. With an estimated 390 million infections per year, the four serotypes of dengue virus (DENV) cause the most important mosquito-borne viral disease in humans. The dengue vaccine Dengvaxia was licensed; however, its low efficacy among dengue-naive individuals and increased risk of causing severe dengue in children highlight the need for a better understanding of the role of human antibodies in immunity against DENV. DENV suspensions contain mature, immature, and partially immature particles. We investigated the binding of 22 human monoclonal antibodies (MAbs) to the DENV envelope protein on particles with different maturation states. Potently neutralizing MAbs had higher relative maximum binding and avidity to mature particles than weakly neutralizing MAbs. This was supported by analysis of MAb repertoires and polyclonal sera from patients with primary DENV infection. Together, these findings suggest that mature particles may be the optimal form of presentation of the envelope protein to induce more potent neutralizing antibodies against DENV.
Copyright © 2018 American Society for Microbiology.
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10 MeSH Terms
HIV: Antiviral action countered by Nef.
Aiken C
(2015) Nature 526: 202-3
MeSH Terms: Animals, HIV-1, Host-Pathogen Interactions, Humans, Membrane Glycoproteins, Membrane Proteins, Neoplasm Proteins, Receptors, Cell Surface, Virion, nef Gene Products, Human Immunodeficiency Virus
Added February 4, 2016
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10 MeSH Terms
Association of VH4-59 Antibody Variable Gene Usage with Recognition of an Immunodominant Epitope on the HIV-1 Gag Protein.
Chukwuma VU, Hicar MD, Chen X, Nicholas KJ, Joyner A, Kalams SA, Landucci G, Forthal DN, Spearman PW, Crowe JE
(2015) PLoS One 10: e0133509
MeSH Terms: Amino Acid Sequence, Antibodies, Monoclonal, B-Lymphocytes, Gene Products, gag, Genes, Immunoglobulin, HIV Antibodies, HIV Infections, HIV-1, Humans, Immunodominant Epitopes, Molecular Sequence Data, Neutralization Tests, T-Lymphocytes, Virion
Show Abstract · Added January 26, 2016
The human antibody response against HIV-1 infection recognizes diverse antigenic subunits of the virion, and includes a high level of antibodies to the Gag protein. We report here the isolation and characterization of a subset of Gag-specific human monoclonal antibodies (mAbs) that were prevalent in the antibody repertoire of an HIV-infected individual. Several lineages of Gag-specifc mAbs were encoded by a single antibody heavy chain variable region, VH4-59, and a representative antibody from this group designated mAb 3E4 recognized a linear epitope on the globular head of the p17 subunit of Gag. We found no evidence that mAb 3E4 exhibited any function in laboratory studies aimed at elucidating the immunologic activity, including assays for neutralization, Ab-dependent cell-mediated virus inhibition, or enhanced T cell reactivity caused by Gag-3E4 complexes. The findings suggest this immunodominant epitope in Gag protein, which is associated with VH4-59 germline gene usage, may induce a high level of B cells that encode binding but non-functional antibodies that occupy significant repertoire space following HIV infection. The studies define an additional specific molecular mechanism in the immune distraction activity of the HIV virion.
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14 MeSH Terms
Diminished reovirus capsid stability alters disease pathogenesis and littermate transmission.
Doyle JD, Stencel-Baerenwald JE, Copeland CA, Rhoads JP, Brown JJ, Boyd KL, Atkinson JB, Dermody TS
(2015) PLoS Pathog 11: e1004693
MeSH Terms: Animals, Capsid, Capsid Proteins, Mice, Mutation, Orthoreovirus, Mammalian, Virion, Virus Assembly
Show Abstract · Added February 4, 2016
Reovirus is a nonenveloped mammalian virus that provides a useful model system for studies of viral infections in the young. Following internalization into host cells, the outermost capsid of reovirus virions is removed by endosomal cathepsin proteases. Determinants of capsid disassembly kinetics reside in the viral σ3 protein. However, the contribution of capsid stability to reovirus-induced disease is unknown. In this study, we found that mice inoculated intramuscularly with a serotype 3 reovirus containing σ3-Y354H, a mutation that reduces viral capsid stability, succumbed at a higher rate than those infected with wild-type virus. At early times after inoculation, σ3-Y354H virus reached higher titers than wild-type virus at several sites within the host. Animals inoculated perorally with a serotype 1 reassortant reovirus containing σ3-Y354H developed exaggerated myocarditis accompanied by elaboration of pro-inflammatory cytokines. Surprisingly, unchallenged littermates of mice infected with σ3-Y354H virus displayed higher titers in the intestine, heart, and brain than littermates of mice inoculated with wild-type virus. Together, these findings suggest that diminished capsid stability enhances reovirus replication, dissemination, lethality, and host-to-host spread, establishing a new virulence determinant for nonenveloped viruses.
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8 MeSH Terms
The Nogo receptor NgR1 mediates infection by mammalian reovirus.
Konopka-Anstadt JL, Mainou BA, Sutherland DM, Sekine Y, Strittmatter SM, Dermody TS
(2014) Cell Host Microbe 15: 681-91
MeSH Terms: Animals, CHO Cells, Capsid Proteins, Cell Adhesion Molecules, Cell Membrane, Cricetulus, GPI-Linked Proteins, Host-Pathogen Interactions, Humans, Mice, Mutant Strains, Myelin Proteins, Neuraminidase, Neurons, Nogo Receptor 1, Receptors, Cell Surface, Reoviridae, Reoviridae Infections, Virion
Show Abstract · Added January 21, 2015
Neurotropic viruses, including mammalian reovirus, must disseminate from an initial site of replication to the central nervous system (CNS), often binding multiple receptors to facilitate systemic spread. Reovirus engages junctional adhesion molecule A (JAM-A) to disseminate hematogenously. However, JAM-A is dispensable for reovirus replication in the CNS. We demonstrate that reovirus binds Nogo receptor NgR1, a leucine-rich repeat protein expressed in the CNS, to infect neurons. Expression of NgR1 confers reovirus binding and infection of nonsusceptible cells. Incubating reovirus virions with soluble NgR1 neutralizes infectivity. Blocking NgR1 on transfected cells or primary cortical neurons abrogates reovirus infection. Concordantly, reovirus infection is ablated in primary cortical neurons derived from NgR1 null mice. Reovirus virions bind to soluble JAM-A and NgR1, while infectious disassembly intermediates (ISVPs) bind only to JAM-A. These results suggest that reovirus uses different capsid components to bind distinct cell-surface molecules, engaging independent receptors to facilitate spread and tropism.
Copyright © 2014 Elsevier Inc. All rights reserved.
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18 MeSH Terms
Predicted structure and domain organization of rotavirus capping enzyme and innate immune antagonist VP3.
Ogden KM, Snyder MJ, Dennis AF, Patton JT
(2014) J Virol 88: 9072-85
MeSH Terms: Amino Acid Sequence, Animals, Capsid Proteins, Catalytic Domain, Cell Line, Immunity, Innate, Molecular Sequence Data, Orbivirus, Phylogeny, Protein Structure, Tertiary, Rotavirus, Rotavirus Infections, Sequence Alignment, Sf9 Cells, Spodoptera, Transcription, Genetic, Virion
Show Abstract · Added April 26, 2017
UNLABELLED - Rotaviruses and orbiviruses are nonturreted Reoviridae members. The rotavirus VP3 protein is a multifunctional capping enzyme and antagonist of the interferon-induced cellular oligoadenylate synthetase-RNase L pathway. Despite mediating important processes, VP3 is the sole protein component of the rotavirus virion whose structure remains unknown. In the current study, we used sequence alignment and homology modeling to identify features common to nonturreted Reoviridae capping enzymes and to predict the domain organization, structure, and active sites of rotavirus VP3. Our results suggest that orbivirus and rotavirus capping enzymes share a domain arrangement similar to that of the bluetongue virus capping enzyme. Sequence alignments revealed conserved motifs and suggested that rotavirus and orbivirus capping enzymes contain a variable N-terminal domain, a central guanine-N7-methyltransferase domain that contains an additional inserted domain, and a C-terminal guanylyltransferase and RNA 5'-triphosphatase domain. Sequence conservation and homology modeling suggested that the insertion in the guanine-N7-methyltransferase domain is a ribose-2'-O-methyltransferase domain for most rotavirus species. Our analyses permitted putative identification of rotavirus VP3 active-site residues, including those that form the ribose-2'-O-methyltransferase catalytic tetrad, interact with S-adenosyl-l-methionine, and contribute to autoguanylation. Previous reports have indicated that group A rotavirus VP3 contains a C-terminal 2H-phosphodiesterase domain that can cleave 2'-5' oligoadenylates, thereby preventing RNase L activation. Our results suggest that a C-terminal phosphodiesterase domain is present in the capping enzymes from two additional rotavirus species. Together, these findings provide insight into a poorly understood area of rotavirus biology and are a springboard for future biochemical and structural studies of VP3.
IMPORTANCE - Rotaviruses are an important cause of severe diarrheal disease. The rotavirus VP3 protein caps viral mRNAs and helps combat cellular innate antiviral defenses, but little is known about its structure or enzymatic mechanisms. In this study, we used sequence- and structure-based alignments with related proteins to predict the structure of VP3 and identify enzymatic domains and active sites therein. This work provides insight into the mechanisms of rotavirus transcription and evasion of host innate immune defenses. An improved understanding of these processes may aid our ability to develop rotavirus vaccines and therapeutics.
Copyright © 2014, American Society for Microbiology. All Rights Reserved.
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17 MeSH Terms
Cocaine enhances HIV-1-induced CD4(+) T-cell apoptosis: implications in disease progression in cocaine-abusing HIV-1 patients.
Pandhare J, Addai AB, Mantri CK, Hager C, Smith RM, Barnett L, Villalta F, Kalams SA, Dash C
(2014) Am J Pathol 184: 927-936
MeSH Terms: Apoptosis, CD4-Positive T-Lymphocytes, Cell Separation, Cocaine, Cocaine-Related Disorders, Disease Progression, Dopamine Uptake Inhibitors, Flow Cytometry, HIV Infections, HIV-1, Humans, Virion
Show Abstract · Added January 20, 2015
Substance abuse is a major barrier in eradication of the HIV epidemic because it serves as a powerful cofactor for viral transmission, disease progression, and AIDS-related mortality. Cocaine, one of the commonly abused drugs among HIV-1 patients, has been suggested to accelerate HIV disease progression. However, the underlying mechanism remains largely unknown. Therefore, we tested whether cocaine augments HIV-1-associated CD4(+) T-cell decline, a predictor of HIV disease progression. We examined apoptosis of resting CD4(+) T cells from HIV-1-negative and HIV-1-positive donors in our study, because decline of uninfected cells plays a major role in HIV-1 disease progression. Treatment of resting CD4(+) T cells with cocaine (up to 100 μmol/L concentrations) did not induce apoptosis, but 200 to 1000 μmol/L cocaine induced apoptosis in a dose-dependent manner. Notably, treatment of CD4(+) T cells isolated from healthy donors with both HIV-1 virions and cocaine significantly increased apoptosis compared with the apoptosis induced by cocaine or virions alone. Most important, our biochemical data suggest that cocaine induces CD4(+) T-cell apoptosis by increasing intracellular reactive oxygen species levels and inducing mitochondrial depolarization. Collectively, our results provide evidence of a synergy between cocaine and HIV-1 on CD4(+) T-cell apoptosis that may, in part, explain the accelerated disease observed in HIV-1-infected drug abusers.
Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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12 MeSH Terms
Intracellular neutralization of a virus using a cell-penetrating molecular transporter.
Sapparapu G, Sims AL, Aiyegbo MS, Shaikh FY, Harth EM, Crowe JE
(2014) Nanomedicine (Lond) 9: 1613-24
MeSH Terms: Animals, Antibodies, Antibodies, Monoclonal, Biological Transport, Capsid Proteins, Cytoplasm, Dendrimers, Enzyme-Linked Immunosorbent Assay, Gene Transfer Techniques, HIV-1, Humans, Immunoglobulin Fragments, Kidney, Macaca mulatta, Magnetic Resonance Spectroscopy, Microscopy, Confocal, Nanomedicine, Neutralization Tests, Peptides, RNA, Small Interfering, Rotavirus, Virion, Viruses
Show Abstract · Added March 7, 2014
AIMS - Antibodies are the principal mediator of immunity against reinfection with viruses. Antibodies typically neutralize viruses by binding to virion particles in solution prior to attachment to susceptible cells. Once viruses enter cells, conventional antibodies cannot inhibit virus infection or replication. It is desirable to develop an efficient and nontoxic method for the introduction of virus-inhibiting antibodies into cells.
MATERIALS & METHODS - In this article, we report a new method for the delivery of small recombinant antibody fragments into virus-infected cells using a dendrimer-based molecular transporter.
RESULTS & CONCLUSION - The construct penetrated virus-infected cells efficiently and inhibited virus replication. This method provides a novel approach for the immediate delivery of inhibitory antibodies directed to virus proteins that are exposed only in the intracellular environment. This approach circumvents the current and rather complicated expression of inhibitory antibodies in cells following gene transfer.
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2 Members
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23 MeSH Terms
INI1/hSNF5-interaction defective HIV-1 IN mutants exhibit impaired particle morphology, reverse transcription and integration in vivo.
Mathew S, Nguyen M, Wu X, Pal A, Shah VB, Prasad VR, Aiken C, Kalpana GV
(2013) Retrovirology 10: 66
MeSH Terms: Cell Line, Chromosomal Proteins, Non-Histone, DNA-Binding Proteins, HIV Integrase, HIV-1, Host-Pathogen Interactions, Humans, Microscopy, Electron, Transmission, Reverse Transcription, SMARCB1 Protein, Transcription Factors, Virion, Virus Assembly, Virus Integration
Show Abstract · Added May 27, 2014
BACKGROUND - Retroviral integrase catalyzes integration of viral DNA into the host genome. Integrase interactor (INI)1/hSNF5 is a host factor that binds to HIV-1 IN within the context of Gag-Pol and is specifically incorporated into HIV-1 virions during assembly. Previous studies have indicated that INI1/hSNF5 is required for late events in vivo and for integration in vitro. To determine the effects of disrupting the IN-INI1 interaction on the assembly and infectivity of HIV-1 particles, we isolated mutants of IN that are defective for binding to INI1/hSNF5 and tested their effects on HIV-1 replication.
RESULTS - A reverse yeast two-hybrid system was used to identify INI1-interaction defective IN mutants (IID-IN). Since protein-protein interactions depend on the surface residues, the IID-IN mutants that showed high surface accessibility on IN crystal structures (K71R, K111E, Q137R, D202G, and S147G) were selected for further study. In vitro interaction studies demonstrated that IID-IN mutants exhibit variable degrees of interaction with INI1. The mutations were engineered into HIV-1(NL4-3) and HIV-Luc viruses and tested for their effects on virus replication. HIV-1 harboring IID-IN mutations were defective for replication in both multi- and single-round infection assays. The infectivity defects were correlated to the degree of INI1 interaction of the IID-IN mutants. Highly defective IID-IN mutants were blocked at early and late reverse transcription, whereas partially defective IID-IN mutants proceeded through reverse transcription and nuclear localization, but were partially impaired for integration. Electron microscopic analysis of mutant particles indicated that highly interaction-defective IID-IN mutants produced morphologically aberrant virions, whereas the partially defective mutants produced normal virions. All of the IID-IN mutant particles exhibited normal capsid stability and reverse transcriptase activity in vitro.
CONCLUSIONS - Our results demonstrate that a severe defect in IN-INI1 interaction is associated with production of defective particles and a subsequent defect in post-entry events. A partial defect in IN-INI1 interaction leads to production of normal virions that are partially impaired for early events including integration. Our studies suggest that proper interaction of INI1 with IN within Gag-Pol is necessary for proper HIV-1 morphogenesis and integration.
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14 MeSH Terms
Human rotavirus VP6-specific antibodies mediate intracellular neutralization by binding to a quaternary structure in the transcriptional pore.
Aiyegbo MS, Sapparapu G, Spiller BW, Eli IM, Williams DR, Kim R, Lee DE, Liu T, Li S, Woods VL, Nannemann DP, Meiler J, Stewart PL, Crowe JE
(2013) PLoS One 8: e61101
MeSH Terms: Amino Acid Sequence, Animals, Antibodies, Monoclonal, Antibodies, Viral, Antigens, Viral, B-Lymphocytes, Caco-2 Cells, Capsid Proteins, Cell Line, Epitopes, HEK293 Cells, Host-Pathogen Interactions, Humans, Immunoglobulin A, Models, Molecular, Molecular Sequence Data, Neutralization Tests, Protein Binding, Protein Structure, Tertiary, Rotavirus, Rotavirus Infections, Sequence Homology, Amino Acid, Transcription, Genetic, Virion, Virus Replication
Show Abstract · Added May 29, 2014
Several live attenuated rotavirus (RV) vaccines have been licensed, but the mechanisms of protective immunity are still poorly understood. The most frequent human B cell response is directed to the internal protein VP6 on the surface of double-layered particles, which is normally exposed only in the intracellular environment. Here, we show that the canonical VP6 antibodies secreted by humans bind to such particles and inhibit viral transcription. Polymeric IgA RV antibodies mediated an inhibitory effect against virus replication inside cells during IgA transcytosis. We defined the recognition site on VP6 as a quaternary epitope containing a high density of charged residues. RV human mAbs appear to bind to a negatively-charged patch on the surface of the Type I channel in the transcriptionally active particle, and they sterically block the channel. This unique mucosal mechanism of viral neutralization, which is not apparent from conventional immunoassays, may contribute significantly to human immunity to RV.
1 Communities
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25 MeSH Terms