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Therapeutic administration of a recombinant human monoclonal antibody reduces the severity of chikungunya virus disease in rhesus macaques.
Broeckel R, Fox JM, Haese N, Kreklywich CN, Sukulpovi-Petty S, Legasse A, Smith PP, Denton M, Corvey C, Krishnan S, Colgin LMA, Ducore RM, Lewis AD, Axthelm MK, Mandron M, Cortez P, Rothblatt J, Rao E, Focken I, Carter K, Sapparapau G, Crowe JE, Diamond MS, Streblow DN
(2017) PLoS Negl Trop Dis 11: e0005637
MeSH Terms: Animals, Antibodies, Monoclonal, Antibodies, Viral, B-Lymphocytes, Chikungunya Fever, Chikungunya virus, Disease Models, Animal, Drug Evaluation, Preclinical, Immunologic Factors, Macaca mulatta, T-Lymphocytes, Treatment Outcome
Show Abstract · Added March 14, 2018
Chikungunya virus (CHIKV) is a mosquito-borne virus that causes a febrile syndrome in humans associated with acute and chronic debilitating joint and muscle pain. Currently no licensed vaccines or therapeutics are available to prevent or treat CHIKV infections. We recently isolated a panel of potently neutralizing human monoclonal antibodies (mAbs), one (4N12) of which exhibited prophylactic and post-exposure therapeutic activity against CHIKV in immunocompromised mice. Here, we describe the development of an engineered CHIKV mAb, designated SVIR001, that has similar antigen binding and neutralization profiles to its parent, 4N12. Because therapeutic administration of SVIR001 in immunocompetent mice significantly reduced viral load in joint tissues, we evaluated its efficacy in a rhesus macaque model of CHIKV infection. Rhesus macaques that were treated after infection with SVIR001 showed rapid elimination of viremia and less severe joint infiltration and disease compared to animals treated with SVIR002, an isotype control mAb. SVIR001 reduced viral burden at the site of infection and at distant sites and also diminished the numbers of activated innate immune cells and levels of pro-inflammatory cytokines and chemokines. SVIR001 therapy; however, did not substantively reduce the induction of CHIKV-specific B or T cell responses. Collectively, these results show promising therapeutic activity of a human anti-CHIKV mAb in rhesus macaques and provide proof-of-principle for its possible use in humans to treat active CHIKV infections.
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12 MeSH Terms
Therapy with CTLA4-Ig and an antiviral monoclonal antibody controls chikungunya virus arthritis.
Miner JJ, Cook LE, Hong JP, Smith AM, Richner JM, Shimak RM, Young AR, Monte K, Poddar S, Crowe JE, Lenschow DJ, Diamond MS
(2017) Sci Transl Med 9:
MeSH Terms: Abatacept, Animals, Antibodies, Neutralizing, Antibodies, Viral, Antiviral Agents, Arthritis, Infectious, Chemokines, Chikungunya Fever, Cytokines, Leukocytes, Mice, Mice, Inbred C57BL, Viral Load
Show Abstract · Added April 13, 2017
In 2013, chikungunya virus (CHIKV) transmission was documented in the Western Hemisphere, and the virus has since spread throughout the Americas with more than 1.8 million people infected in more than 40 countries. CHIKV targets the joints, resulting in symmetric polyarthritis that clinically mimics rheumatoid arthritis and can endure for months to years. At present, no approved treatment is effective in preventing or controlling CHIKV infection or disease. We treated mice with eight different disease-modifying antirheumatic drugs and identified CLTA4-Ig (abatacept) and tofacitinib as candidate therapies based on their ability to decrease acute joint swelling. CTLA4-Ig reduced T cell accumulation in the joints of infected animals without affecting viral infection. Whereas monotherapy with CTLA4-Ig or a neutralizing anti-CHIKV human monoclonal antibody provided partial clinical improvement, therapy with both abolished swelling and markedly reduced levels of chemokines, proinflammatory cytokines, and infiltrating leukocytes. Thus, combination CTLA4-Ig and antiviral antibody therapy controls acute CHIKV infection and arthritis and may be a candidate for testing in humans.
Copyright © 2017, American Association for the Advancement of Science.
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13 MeSH Terms
The Molecular Basis for the Lack of Inflammatory Responses in Mouse Embryonic Stem Cells and Their Differentiated Cells.
D'Angelo W, Gurung C, Acharya D, Chen B, Ortolano N, Gama V, Bai F, Guo YL
(2017) J Immunol 198: 2147-2155
MeSH Terms: Animals, Cell Differentiation, Chikungunya Fever, Chikungunya virus, Embryonic Stem Cells, Immunity, Inflammation, Interferons, Lipopolysaccharides, Mice, Mice, Inbred DBA, NF-kappa B, RAW 264.7 Cells, Tumor Necrosis Factor-alpha, Virus Diseases
Show Abstract · Added July 10, 2017
We reported previously that mouse embryonic stem cells do not have a functional IFN-based antiviral mechanism. The current study extends our investigation to the inflammatory response in mouse embryonic stem cells and mouse embryonic stem cell-differentiated cells. We demonstrate that LPS, TNF-α, and viral infection, all of which induce robust inflammatory responses in naturally differentiated cells, failed to activate NF-κB, the key transcription factor that mediates inflammatory responses, and were unable to induce the expression of inflammatory genes in mouse embryonic stem cells. Similar results were obtained in human embryonic stem cells. In addition to the inactive state of NF-κB, the deficiency in the inflammatory response in mouse embryonic stem cells is also attributed to the lack of functional receptors for LPS and TNF-α. In vitro differentiation can trigger the development of the inflammatory response mechanism, as indicated by the transition of NF-κB from its inactive to active state. However, a limited response to TNF-α and viral infection, but not to LPS, was observed in mouse embryonic stem cell-differentiated fibroblasts. We conclude that the inflammatory response mechanism is not active in mouse embryonic stem cells, and in vitro differentiation promotes only partial development of this mechanism. Together with our previous studies, the findings described in this article demonstrate that embryonic stem cells are fundamentally different from differentiated somatic cells in their innate immunity, which may have important implications in developmental biology, immunology, and embryonic stem cell-based regenerative medicine.
Copyright © 2017 by The American Association of Immunologists, Inc.
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15 MeSH Terms
Pathogenic Chikungunya Virus Evades B Cell Responses to Establish Persistence.
Hawman DW, Fox JM, Ashbrook AW, May NA, Schroeder KMS, Torres RM, Crowe JE, Dermody TS, Diamond MS, Morrison TE
(2016) Cell Rep 16: 1326-1338
MeSH Terms: Amino Acids, Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, B-Lymphocytes, Chikungunya Fever, Chikungunya virus, Glycoproteins, Humans, Mice, Mice, Inbred C57BL, Viral Envelope Proteins
Show Abstract · Added April 13, 2017
Chikungunya virus (CHIKV) and related alphaviruses cause epidemics of acute and chronic musculoskeletal disease. To investigate the mechanisms underlying the failure of immune clearance of CHIKV, we studied mice infected with an attenuated CHIKV strain (181/25) and the pathogenic parental strain (AF15561), which differ by five amino acids. Whereas AF15561 infection of wild-type mice results in viral persistence in joint tissues, 181/25 is cleared. In contrast, 181/25 infection of μMT mice lacking mature B cells results in viral persistence in joint tissues, suggesting that virus-specific antibody is required for clearance of infection. Mapping studies demonstrated that a highly conserved glycine at position 82 in the A domain of the E2 glycoprotein impedes clearance and neutralization of multiple CHIKV strains. Remarkably, murine and human antibodies targeting E2 domain B failed to neutralize pathogenic CHIKV strains efficiently. Our data suggest that pathogenic CHIKV strains evade E2 domain-B-neutralizing antibodies to establish persistence.
Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.
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13 MeSH Terms
Cryo-EM structures elucidate neutralizing mechanisms of anti-chikungunya human monoclonal antibodies with therapeutic activity.
Long F, Fong RH, Austin SK, Chen Z, Klose T, Fokine A, Liu Y, Porta J, Sapparapu G, Akahata W, Doranz BJ, Crowe JE, Diamond MS, Rossmann MG
(2015) Proc Natl Acad Sci U S A 112: 13898-903
MeSH Terms: Antibodies, Monoclonal, Antibodies, Neutralizing, Chikungunya Fever, Chikungunya virus, Cryoelectron Microscopy, Humans, Protein Conformation
Show Abstract · Added January 26, 2016
Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes severe acute and chronic disease in humans. Although highly inhibitory murine and human monoclonal antibodies (mAbs) have been generated, the structural basis of their neutralizing activity remains poorly characterized. Here, we determined the cryo-EM structures of chikungunya virus-like particles complexed with antibody fragments (Fab) of two highly protective human mAbs, 4J21 and 5M16, that block virus fusion with host membranes. Both mAbs bind primarily to sites within the A and B domains, as well as to the B domain's β-ribbon connector of the viral glycoprotein E2. The footprints of these antibodies on the viral surface were consistent with results from loss-of-binding studies using an alanine scanning mutagenesis-based epitope mapping approach. The Fab fragments stabilized the position of the B domain relative to the virus, particularly for the complex with 5M16. This finding is consistent with a mechanism of neutralization in which anti-CHIKV mAbs that bridge the A and B domains impede movement of the B domain away from the underlying fusion loop on the E1 glycoprotein and therefore block the requisite pH-dependent fusion of viral and host membranes.
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7 MeSH Terms
Isolation and Characterization of Broad and Ultrapotent Human Monoclonal Antibodies with Therapeutic Activity against Chikungunya Virus.
Smith SA, Silva LA, Fox JM, Flyak AI, Kose N, Sapparapu G, Khomandiak S, Khomadiak S, Ashbrook AW, Kahle KM, Fong RH, Swayne S, Doranz BJ, McGee CE, Heise MT, Pal P, Brien JD, Austin SK, Diamond MS, Dermody TS, Crowe JE
(2015) Cell Host Microbe 18: 86-95
MeSH Terms: Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Chemoprevention, Chikungunya Fever, Chikungunya virus, Disease Models, Animal, Humans, Immunization, Passive, Inhibitory Concentration 50, Mice, Protein Binding, Survival Analysis, Treatment Outcome, Viral Envelope Proteins, Virus Internalization
Show Abstract · Added January 26, 2016
Chikungunya virus (CHIKV) is a mosquito-transmitted RNA virus that causes acute febrile infection associated with polyarthralgia in humans. Mechanisms of protective immunity against CHIKV are poorly understood, and no effective therapeutics or vaccines are available. We isolated and characterized human monoclonal antibodies (mAbs) that neutralize CHIKV infectivity. Among the 30 mAbs isolated, 13 had broad and ultrapotent neutralizing activity (IC50 < 10 ng/ml), and all of these mapped to domain A of the E2 envelope protein. Potent inhibitory mAbs blocked post-attachment steps required for CHIKV membrane fusion, and several were protective in a lethal challenge model in immunocompromised mice, even when administered at late time points after infection. These highly protective mAbs could be considered for prevention or treatment of CHIKV infection, and their epitope location in domain A of E2 could be targeted for rational structure-based vaccine development.
Copyright © 2015 Elsevier Inc. All rights reserved.
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17 MeSH Terms
A single-amino-acid polymorphism in Chikungunya virus E2 glycoprotein influences glycosaminoglycan utilization.
Silva LA, Khomandiak S, Ashbrook AW, Weller R, Heise MT, Morrison TE, Dermody TS
(2014) J Virol 88: 2385-97
MeSH Terms: Alphavirus Infections, Amino Acid Substitution, Animals, CHO Cells, Chikungunya Fever, Chikungunya virus, Chlorocebus aethiops, Cricetinae, Cricetulus, Endosomes, Genotype, Glycosaminoglycans, Heparitin Sulfate, Humans, Hydrogen Bonding, Kinetics, Models, Molecular, Mutation, Polymorphism, Single Nucleotide, Protein Multimerization, Static Electricity, Vero Cells, Viral Envelope Proteins, Virus Attachment, Virus Internalization, Virus Replication
Show Abstract · Added May 20, 2014
UNLABELLED - Chikungunya virus (CHIKV) is a reemerging arbovirus responsible for outbreaks of infection throughout Asia and Africa, causing an acute illness characterized by fever, rash, and polyarthralgia. Although CHIKV infects a broad range of host cells, little is known about how CHIKV binds and gains access to the target cell interior. In this study, we tested whether glycosaminoglycan (GAG) binding is required for efficient CHIKV replication using CHIKV vaccine strain 181/25 and clinical isolate SL15649. Preincubation of strain 181/25, but not SL15649, with soluble GAGs resulted in dose-dependent inhibition of infection. While parental Chinese hamster ovary (CHO) cells are permissive for both strains, neither strain efficiently bound to or infected mutant CHO cells devoid of GAG expression. Although GAGs appear to be required for efficient binding of both strains, they exhibit differential requirements for GAGs, as SL15649 readily infected cells that express excess chondroitin sulfate but that are devoid of heparan sulfate, whereas 181/25 did not. We generated a panel of 181/25 and SL15649 variants containing reciprocal amino acid substitutions at positions 82 and 318 in the E2 glycoprotein. Reciprocal exchange at residue 82 resulted in a phenotype switch; Gly(82) results in efficient infection of mutant CHO cells but a decrease in heparin binding, whereas Arg(82) results in reduced infectivity of mutant cells and an increase in heparin binding. These results suggest that E2 residue 82 is a primary determinant of GAG utilization, which likely mediates attenuation of vaccine strain 181/25.
IMPORTANCE - Chikungunya virus (CHIKV) infection causes a debilitating rheumatic disease that can persist for months to years, and yet there are no licensed vaccines or antiviral therapies. Like other alphaviruses, CHIKV displays broad tissue tropism, which is thought to be influenced by virus-receptor interactions. In this study, we determined that cell-surface glycosaminoglycans are utilized by both a vaccine strain and a clinical isolate of CHIKV to mediate virus binding. We also identified an amino acid polymorphism in the viral E2 attachment protein that influences utilization of glycosaminoglycans. These data enhance an understanding of the viral and host determinants of CHIKV cell entry, which may foster development of new antivirals that act by blocking this key step in viral infection.
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26 MeSH Terms