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Structure-function characterization of three human antibodies targeting the vaccinia virus adhesion molecule D8.
Matho MH, Schlossman A, Gilchuk IM, Miller G, Mikulski Z, Hupfer M, Wang J, Bitra A, Meng X, Xiang Y, Kaever T, Doukov T, Ley K, Crotty S, Peters B, Hsieh-Wilson LC, Crowe JE, Zajonc DM
(2018) J Biol Chem 293: 390-401
MeSH Terms: Antibodies, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Antibody Formation, Antigens, Viral, Cell Adhesion Molecules, Crystallography, X-Ray, Enzyme-Linked Immunosorbent Assay, Epitopes, Humans, Neutralization Tests, Protein Binding, Structure-Activity Relationship, Vaccinia virus, Viral Envelope Proteins
Show Abstract · Added March 14, 2018
Vaccinia virus (VACV) envelope protein D8 is one of three glycosaminoglycan adhesion molecules and binds to the linear polysaccharide chondroitin sulfate (CS). D8 is also a target for neutralizing antibody responses that are elicited by the smallpox vaccine, which has enabled the first eradication of a human viral pathogen and is a useful model for studying antibody responses. However, to date, VACV epitopes targeted by human antibodies have not been characterized at atomic resolution. Here, we characterized the binding properties of several human anti-D8 antibodies and determined the crystal structures of three VACV-mAb variants, VACV-66, VACV-138, and VACV-304, separately bound to D8. Although all these antibodies bound D8 with high affinity and were moderately neutralizing in the presence of complement, VACV-138 and VACV-304 also fully blocked D8 binding to CS-A, the low affinity ligand for D8. VACV-138 also abrogated D8 binding to the high-affinity ligand CS-E, but we observed residual CS-E binding was observed in the presence of VACV-304. Analysis of the VACV-138- and VACV-304-binding sites along the CS-binding crevice of D8, combined with different efficiencies of blocking D8 adhesion to CS-A and CS-E allowed us to propose that D8 has a high- and low-affinity CS-binding region within its central crevice. The crevice is amenable to protein engineering to further enhance both specificity and affinity of binding to CS-E. Finally, a wild-type D8 tetramer specifically bound to structures within the developing glomeruli of the kidney, which express CS-E. We propose that through structure-based protein engineering, an improved D8 tetramer could be used as a potential diagnostic tool to detect expression of CS-E, which is a possible biomarker for ovarian cancer.
© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.
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16 MeSH Terms
Cross-Neutralizing and Protective Human Antibody Specificities to Poxvirus Infections.
Gilchuk I, Gilchuk P, Sapparapu G, Lampley R, Singh V, Kose N, Blum DL, Hughes LJ, Satheshkumar PS, Townsend MB, Kondas AV, Reed Z, Weiner Z, Olson VA, Hammarlund E, Raue HP, Slifka MK, Slaughter JC, Graham BS, Edwards KM, Eisenberg RJ, Cohen GH, Joyce S, Crowe JE
(2016) Cell 167: 684-694.e9
MeSH Terms: Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Antibody Specificity, Cowpox, Cowpox virus, Cross Reactions, Humans, Leukocytes, Mononuclear, Monkeypox, Monkeypox virus, Poxviridae Infections, Smallpox, Vaccinia, Vaccinia virus, Variola virus
Show Abstract · Added April 13, 2017
Monkeypox (MPXV) and cowpox (CPXV) are emerging agents that cause severe human infections on an intermittent basis, and variola virus (VARV) has potential for use as an agent of bioterror. Vaccinia immune globulin (VIG) has been used therapeutically to treat severe orthopoxvirus infections but is in short supply. We generated a large panel of orthopoxvirus-specific human monoclonal antibodies (Abs) from immune subjects to investigate the molecular basis of broadly neutralizing antibody responses for diverse orthopoxviruses. Detailed analysis revealed the principal neutralizing antibody specificities that are cross-reactive for VACV, CPXV, MPXV, and VARV and that are determinants of protection in murine challenge models. Optimal protection following respiratory or systemic infection required a mixture of Abs that targeted several membrane proteins, including proteins on enveloped and mature virion forms of virus. This work reveals orthopoxvirus targets for human Abs that mediate cross-protective immunity and identifies new candidate Ab therapeutic mixtures to replace VIG.
Copyright © 2016 Elsevier Inc. All rights reserved.
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16 MeSH Terms
Viral infection causes a shift in the self peptide repertoire presented by human MHC class I molecules.
Spencer CT, Bezbradica JS, Ramos MG, Arico CD, Conant SB, Gilchuk P, Gray JJ, Zheng M, Niu X, Hildebrand W, Link AJ, Joyce S
(2015) Proteomics Clin Appl 9: 1035-52
MeSH Terms: Amino Acid Sequence, Antigen Presentation, Cell Line, Histocompatibility Antigens Class I, Humans, Molecular Sequence Data, Oncogenes, Peptides, Proteomics, Vaccinia virus
Show Abstract · Added February 15, 2016
PURPOSE - MHC class I presentation of peptides allows T cells to survey the cytoplasmic protein milieu of host cells. During infection, presentation of self peptides is, in part, replaced by presentation of microbial peptides. However, little is known about the self peptides presented during infection, despite the fact that microbial infections alter host cell gene expression patterns and protein metabolism.
EXPERIMENTAL DESIGN - The self peptide repertoire presented by HLA-A*01;01, HLA-A*02;01, HLA-B*07;02, HLA-B*35;01, and HLA-B*45;01 (where HLA is human leukocyte antigen) was determined by tandem MS before and after vaccinia virus infection.
RESULTS - We observed a profound alteration in the self peptide repertoire with hundreds of self peptides uniquely presented after infection for which we have coined the term "self peptidome shift." The fraction of novel self peptides presented following infection varied for different HLA class I molecules. A large part (approximately 40%) of the self peptidome shift arose from peptides derived from type I interferon-inducible genes, consistent with cellular responses to viral infection. Interestingly, approximately 12% of self peptides presented after infection showed allelic variation when searched against approximately 300 human genomes.
CONCLUSION AND CLINICAL RELEVANCE - Self peptidome shift in a clinical transplant setting could result in alloreactivity by presenting new self peptides in the context of infection-induced inflammation.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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10 MeSH Terms
Specificity and 6-month durability of immune responses induced by DNA and recombinant modified vaccinia Ankara vaccines expressing HIV-1 virus-like particles.
Goepfert PA, Elizaga ML, Seaton K, Tomaras GD, Montefiori DC, Sato A, Hural J, DeRosa SC, Kalams SA, McElrath MJ, Keefer MC, Baden LR, Lama JR, Sanchez J, Mulligan MJ, Buchbinder SP, Hammer SM, Koblin BA, Pensiero M, Butler C, Moss B, Robinson HL, HVTN 205 Study Group, National Institutes of Allergy and Infectious Diseases HIV Vaccines Trials Network
(2014) J Infect Dis 210: 99-110
MeSH Terms: AIDS Vaccines, Adolescent, Adult, Drug Carriers, Female, HIV Antibodies, HIV-1, Humans, Male, Middle Aged, Placebos, T-Lymphocytes, Time Factors, Vaccines, Synthetic, Vaccines, Virus-Like Particle, Vaccinia virus, Young Adult, env Gene Products, Human Immunodeficiency Virus
Show Abstract · Added January 20, 2015
BACKGROUND - Clade B DNA and recombinant modified vaccinia Ankara (MVA) vaccines producing virus-like particles displaying trimeric membrane-bound envelope glycoprotein (Env) were tested in a phase 2a trial in human immunodeficiency virus (HIV)-uninfected adults for safety, immunogenicity, and 6-month durability of immune responses.
METHODS - A total of 299 individuals received 2 doses of JS7 DNA vaccine and 2 doses of MVA/HIV62B at 0, 2, 4, and 6 months, respectively (the DDMM regimen); 3 doses of MVA/HIV62B at 0, 2, and 6 months (the MMM regimen); or placebo injections.
RESULTS - At peak response, 93.2% of the DDMM group and 98.4% of the MMM group had binding antibodies for Env. These binding antibodies were more frequent and of higher magnitude for the transmembrane subunit (gp41) than the receptor-binding subunit (gp120) of Env. For both regimens, response rates were higher for CD4(+) T cells (66.4% in the DDMM group and 43.1% in the MMM group) than for CD8(+) T cells (21.8% in the DDMM group and 14.9% in the MMM group). Responding CD4(+) and CD8(+) T cells were biased toward Gag, and >70% produced 2 or 3 of the 4 cytokines evaluated (ie, interferon γ, interleukin 2, tumor necrosis factor α, and granzyme B). Six months after vaccination, the magnitudes of antibodies and T-cell responses had decreased by <3-fold.
CONCLUSIONS - DDMM and MMM vaccinations with virus-like particle-expressing immunogens elicited durable antibody and T-cell responses.
© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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18 MeSH Terms
Discovering naturally processed antigenic determinants that confer protective T cell immunity.
Gilchuk P, Spencer CT, Conant SB, Hill T, Gray JJ, Niu X, Zheng M, Erickson JJ, Boyd KL, McAfee KJ, Oseroff C, Hadrup SR, Bennink JR, Hildebrand W, Edwards KM, Crowe JE, Williams JV, Buus S, Sette A, Schumacher TN, Link AJ, Joyce S
(2013) J Clin Invest 123: 1976-87
MeSH Terms: Animals, Antigen Presentation, Antigens, CD8-Positive T-Lymphocytes, Epitopes, Epitopes, T-Lymphocyte, HeLa Cells, Histocompatibility Antigens Class I, Humans, Immunodominant Epitopes, Mass Spectrometry, Mice, Mice, Transgenic, Peptides, Phenotype, T-Lymphocytes, Vaccinia virus
Show Abstract · Added March 20, 2014
CD8+ T cells (TCD8) confer protective immunity against many infectious diseases, suggesting that microbial TCD8 determinants are promising vaccine targets. Nevertheless, current T cell antigen identification approaches do not discern which epitopes drive protective immunity during active infection - information that is critical for the rational design of TCD8-targeted vaccines. We employed a proteomics-based approach for large-scale discovery of naturally processed determinants derived from a complex pathogen, vaccinia virus (VACV), that are presented by the most frequent representatives of four major HLA class I supertypes. Immunologic characterization revealed that many previously unidentified VACV determinants were recognized by smallpox-vaccinated human peripheral blood cells in a variegated manner. Many such determinants were recognized by HLA class I-transgenic mouse immune TCD8 too and elicited protective TCD8 immunity against lethal intranasal VACV infection. Notably, efficient processing and stable presentation of immune determinants as well as the availability of naive TCD8 precursors were sufficient to drive a multifunctional, protective TCD8 response. Our approach uses fundamental insights into T cell epitope processing and presentation to define targets of protective TCD8 immunity within human pathogens that have complex proteomes, suggesting that this approach has general applicability in vaccine sciences.
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17 MeSH Terms
Safety, immunogenicity, and surrogate markers of clinical efficacy for modified vaccinia Ankara as a smallpox vaccine in HIV-infected subjects.
Greenberg RN, Overton ET, Haas DW, Frank I, Goldman M, von Krempelhuber A, Virgin G, Bädeker N, Vollmar J, Chaplin P
(2013) J Infect Dis 207: 749-58
MeSH Terms: Adolescent, Adult, Antibodies, Viral, Biomarkers, Drug-Related Side Effects and Adverse Reactions, Female, HIV Infections, Humans, Immunologic Memory, Male, Middle Aged, Smallpox, Smallpox Vaccine, Vaccinia virus, Young Adult
Show Abstract · Added March 13, 2015
BACKGROUND - Human immunodeficiency virus (HIV)-infected persons are at higher risk for serious complications associated with traditional smallpox vaccines. Alternative smallpox vaccines with an improved safety profile would address this unmet medical need.
METHODS - The safety and immunogenicity of modified vaccinia Ankara (MVA) was assessed in 91 HIV-infected adult subjects (CD4(+) T-cell counts, ≥350 cells/mm(3)) and 60 uninfected volunteers. The primary objectives were to evaluate the safety of MVA and immunogenicity in HIV-infected and uninfected subjects. As a measure of the potential efficacy of MVA, the ability to boost the memory response in people previously vaccinated against smallpox was evaluated by the inclusion of vaccinia-experienced HIV-infected and HIV-uninfected subjects.
RESULTS - MVA was well tolerated and immunogenic in all subjects. Antibody responses were comparable between uninfected and HIV-infected populations, with only 1 significantly lower total antibody titer at 2 weeks after the second vaccination, while no significant differences were observed for neutralizing antibodies. MVA rapidly boosted the antibody responses in vaccinia-experienced subjects, supporting the efficacy of MVA against variola.
CONCLUSIONS - MVA is a promising candidate as a safer smallpox vaccine, even for immunocompromised individuals, a group for whom current smallpox vaccines have an unacceptable safety profile.
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15 MeSH Terms
Unusual features of vaccinia virus extracellular virion form neutralization resistance revealed in human antibody responses to the smallpox vaccine.
Benhnia MR, Maybeno M, Blum D, Aguilar-Sino R, Matho M, Meng X, Head S, Felgner PL, Zajonc DM, Koriazova L, Kato S, Burton DR, Xiang Y, Crowe JE, Peters B, Crotty S
(2013) J Virol 87: 1569-85
MeSH Terms: Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Antigens, Viral, Complement System Proteins, Humans, Neutralization Tests, Smallpox Vaccine, Vaccinia virus, Virion
Show Abstract · Added January 26, 2016
The extracellular virion form (EV) of vaccinia virus (VACV) is essential for viral pathogenesis and is difficult to neutralize with antibodies. Why this is the case and how the smallpox vaccine overcomes this challenge remain incompletely understood. We previously showed that high concentrations of anti-B5 antibodies are insufficient to directly neutralize EV (M. R. Benhnia, et al., J. Virol. 83:1201-1215, 2009). This allowed for at least two possible interpretations: covering the EV surface is insufficient for neutralization, or there are insufficient copies of B5 to allow anti-B5 IgG to cover the whole surface of EV and another viral receptor protein remains active. We endeavored to test these possibilities, focusing on the antibody responses elicited by immunization against smallpox. We tested whether human monoclonal antibodies (MAbs) against the three major EV antigens, B5, A33, and A56, could individually or together neutralize EV. While anti-B5 or anti-A33 (but not anti-A56) MAbs of appropriate isotypes were capable of neutralizing EV in the presence of complement, a mixture of anti-B5, anti-A33, and anti-A56 MAbs was incapable of directly neutralizing EV, even at high concentrations. This remained true when neutralizing the IHD-J strain, which lacks a functional version of the fourth and final known EV surface protein, A34. These immunological data are consistent with the possibility that viral proteins may not be the active component of the EV surface for target cell binding and infectivity. We conclude that the protection afforded by the smallpox vaccine anti-EV response is predominantly mediated not by direct neutralization but by isotype-dependent effector functions, such as complement recruitment for antibodies targeting B5 and A33.
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10 MeSH Terms
Polymorphic variants in the human bile salt export pump (BSEP; ABCB11): functional characterization and interindividual variability.
Ho RH, Leake BF, Kilkenny DM, Meyer Zu Schwabedissen HE, Glaeser H, Kroetz DL, Kim RB
(2010) Pharmacogenet Genomics 20: 45-57
MeSH Terms: ATP Binding Cassette Transporter, Subfamily B, Member 11, ATP-Binding Cassette Transporters, Bile Acids and Salts, Cell Line, Cell Membrane, Gene Expression, HeLa Cells, Humans, Liver, Microscopy, Confocal, Mutagenesis, Site-Directed, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, RNA, Messenger, Recombinant Fusion Proteins, Vaccinia virus
Show Abstract · Added December 5, 2013
OBJECTIVES - Our aims were to identify and functionally characterize coding region nonsynonymous single nucleotide polymorphisms in the hepatic efflux transporter, bile salt export pump (BSEP; ABCB11), and to assess interindividual variability in BSEP expression.
METHODS - We identified 24 single nucleotide polymorphisms, including nine nonsynonymous variants, in ABCB11 from genomic DNA of approximately 250 ethnically diverse healthy individuals using denaturing high-performance liquid chromatography analysis and DNA sequencing. Wild type and variant BSEP were generated and functionally characterized for taurocholate transport activity in vitro in HeLa cells using a recombinant vaccinia-based method. BSEP expression was assessed by real-time mRNA analysis, western blot analysis, and immunofluorescence confocal microscopy.
RESULTS - For the most part, polymorphisms were rare and ethnic-dependent. In vitro functional studies revealed several rare variants, including 616A>G, 1674G>C, 1772A>G, and 3556G>A, to be associated with significantly impaired taurocholate transport activity while the 890A>G variant trended towards impaired function but was not statistically significant. The 3556G>A variant was associated with reduced cell surface to total protein expression compared with wild-type BSEP. Expression of BSEP by mRNA and protein analysis was determined from a bank of human liver samples. Wide interindividual variability was noted in both mRNA (19-fold) and protein (31-fold) expression levels. The common variant 1331T>C was associated with significantly reduced hepatic BSEP mRNA levels.
CONCLUSION - Accordingly, our study indicates there are functionally relevant polymorphisms in ABCB11 which may be of potential relevance in the predisposition to acquired liver disorders such as drug-induced cholestasis.
3 Communities
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16 MeSH Terms
Absence of pharyngeal shedding of vaccinia following smallpox vaccination.
Talbot TR, Peters J, Wright PF, Edwards KM
(2007) Am J Infect Control 35: 486-8
MeSH Terms: Adult, Humans, Middle Aged, Pharynx, Smallpox, Smallpox Vaccine, Specimen Handling, Vaccination, Vaccinia virus, Virus Shedding
Show Abstract · Added April 7, 2010
To examine oral shedding of vaccinia in volunteers who were recently vaccinated against smallpox, pharyngeal swabs were collected for viral culture between days 3 and 5 and days 6 and 8 after vaccination with diluted Sanofi Pasteur smallpox vaccine. From 102 adult volunteers (48 vaccinia-naive, 54 vaccinia-experienced), vaccinia was not detected in any specimen (0/201, 95% confidence interval, 0-1.8), which suggests a lack of oral shedding of vaccinia after immunization. This supports recommendations that individuals who were recently vaccinated against smallpox do not require placement in airborne or droplet precautions.
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10 MeSH Terms
Optimal bandaging of smallpox vaccination sites to decrease the potential for secondary vaccinia transmission without impairing lesion healing.
Talbot TR, Peters J, Yan L, Wright PF, Edwards KM
(2006) Infect Control Hosp Epidemiol 27: 1184-92
MeSH Terms: Adult, Bandages, Humans, Middle Aged, Occlusive Dressings, Smallpox, Smallpox Vaccine, Time Factors, Treatment Outcome, Vaccination, Vaccinia, Vaccinia virus, Wound Healing
Show Abstract · Added April 7, 2010
OBJECTIVE - To assess the optimal method for covering smallpox vaccination sites to prevent transmission of vaccinia.
DESIGN - Randomized, nonblinded clinical trial.
SETTING - Tertiary care medical center.
PARTICIPANTS - Vaccinia-naive and vaccinia-experienced volunteers.
INTERVENTIONS - After vaccination, study participants were randomized to receive 1 of 3 types of bandage: gauze, occlusive with gauze lining, or foam. Vaccination sites were assessed every 3 to 5 days until the lesion healed. During each visit, specimens were obtained from the vaccination site, the bandage surface before removal, and the index finger contralateral to the vaccination site and were cultured for vaccinia. Time to lesion healing was assessed.
RESULTS - All 48 vaccinia-naive and 47 (87%) of 54 vaccinia-experienced participants developed a vesicle or pustule at the injection site 6-11 days after vaccination. Fourteen (14%) of 102 participants had bandage cultures positive for vaccinia. All but 1 of these vaccinia-positive cultures were of a bandage from participants randomized to the gauze bandage group, and all but 3 were of bandages from vaccinia-naive participants. No finger-specimen cultures were positive for vaccinia. One episode of neck autoinoculation occurred in a vaccinia-naive individual who had vaccinia recovered from his gauze bandage on multiple visits. The foam bandage was associated with more local adverse effects (skin irritation and induration). The time to healing did not differ among the bandage groups.
CONCLUSIONS - The potential for transmission of vaccinia from a vaccination site is greater if the site is covered by gauze than if it is covered by occlusive or foam bandages. Use of an occlusive bandage with a gauze lining is the best choice for coverage of smallpox vaccination sites because of a reduced potential for vaccinia transmission and a lower reactogenicity rate. Bandage choice did not affect vaccination lesion healing.
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13 MeSH Terms