rologie i - European Congress of Virology

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5 th European Congress of VirologyThursday 12 th September 2013,15h00 – 17h15WORKSHOP 4: “ADAPTIVE IMMUNITY AND VACCINES”Chairpersons:Ben BERKHOUT (Amsterdam, THE NETHERLAND)& Daniel PINSCHEWER (Geneva, SWITZERLAND)Room Prestige Gratte-CielKEYNOTE:Increasing vaccine immunogenicity via manipulation of vaccinia virusBcl-2-like immunomodulatory proteinsGeoffrey L. SMITH 1 , Hongwei REN 1 , Rebecca P. SUMNER 1 , CarlosMALUQUER DE MOTES 1 , Daniel S. MANSUR 2 , Camilla T.O.BENFIELD 1 , Brian J. FERGUSON 11 Department of Pathology, University of Cambridge, Tennis Court Road,Cambridge CB2 1QP, UNITED KINGDOM; 2 Department of Virology,Faculty of Medicine, Imperial College London, St Mary’s Campus, NorfolkPlace, London W2 1PG, UNITED KINGDOMVaccinia virus (VACV) is the live vaccine used to eradicate smallpox.VACV replicates in the cytoplasm, has a dsDNA genome and encodesmany proteins that block the innate immune response to virus infection.These proteins include a family of proteins with structural similarity to B-cell lymphoma protein 2 (Bcl-2): proteins N1, B14, A52, K7 and F1 havehad their structures solved and proteins N2, A46, C6 and B22/C16 arepredicted to adopt a Bcl-2-like fold. Only proteins F1 and N1 have beendescribed as anti-apoptotic, and instead this family of proteins inhibitssignalling cascades that activate innate immunity. By deleting or mutatingthese proteins, the virulence and immunogenicity of VACV can be altered.Evidence will be presented showing that deletion or mutation of proteinsN1, C6 and K7 causes a reduction in virulence but an increase in virusimmunogenicity. This results in better protection against VACV challengethat is mediated by VACV-specific CD8+ cytotoxic T-cell or natural killer(NK) cell activity.show that CPXV012 inhibits ATP binding to TAP, thereby removing theenergy necessary to drive peptide transport. Using CPXV012 mutants,we identified the key amino acids of CPXV012 that are crucial for bothbinding to and inhibition of TAP. These residues have a strong affinity forphospholipids mimicking the ER membrane, and this property correlates toTAP inhibition. These findings provide insights into protein characteristicsrequired for TAP inhibition by CPXV012, the first viral TAP inhibitoridentified outside the herpesvirus family.REF O50The role of antigen avidity in memory inflation upon MCMV infectionLisa BORKNER 1 , Iryna DEKHTIARENKO 1 , Barbara ADLER 2 , LukaCICIN SAIN 11 Helmholtz Centre for Infection Research, Braunschweig, GERMANY;2 Max von Pettenkofer Institute, München, GERMANYHuman cytomegalovirus (HCMV) induces a strong immune response, withT cells specific for certain epitopes accumulating over time. As CMV isstrictly species specific, murine cytomegalovirus (MCMV) provides anin vivo model for HCMV. MCMV elicits two types of CD8 responses:(1) the conventional response with expansion followed by contractionand memory phase, or (2) the inflationary response, which consists ofan ongoing expansion of effector memory T cells which never contract. Itis not clear whether the difference in immune kinetics for certain epitopesis due to the context of their expression, or due to the nature of the peptide.We recently showed that introducing the herpes simplex virus 1 epitopeSSIEFARL (SL) in context of ie2 (memory inflation) and M45 (conventionalresponse) in MCMV resulted in divergent immune kinetics of the SLspecific CD8 T cell response arguing that inflationary responses depend onthe context of gene expression [I. Dekhtiarenko et al., J Immunol 190 (7)].We address here the question whether the nature of the peptide also playsa role. MCMV mutants containing the low avidity Y chromosome peptideKCSRNRQYL (KNL) in the context of ie2 and M45 have been createdand their CD8 response was compared to the MCMV mutants carrying thehigh avidity peptide SL. While the initial response against KNL was lowerthan that against SL, we still observed an accumulation of KNL specificCD8 T cells when the peptide was inserted in the inflationary epitope.Hence, our data argue that peptide avidity may also contribute to the sizeof the inflationary response.ORAL COMMUNICATIONSREF O49Cowpox virus protein CPXV012 avoids MHC I antigen presentationby blocking ATP binding to TAPRutger LUTEIJN 1 , Wouter VAN LEEUWEN 1 , Daniëlle HORST 1 ,Hanneke HOELEN 1 , Robert Jan LEBBINK 1 , Klaus FRÜH 2 , JacquesNEEFJES 3 , Maaike RESSING 1 , Emmanuel WIERTZ 11 University Medical Center, Utrecht, THE NETHERLANDS; 2 Vaccineand Gene Therapy Institute, Beaverton, UNITED STATES OF AMERICA;3 The Netherlands Cancer Institute, Amsterdam, THE NETHERLANDSViral antigen presentation by MHC class I molecules is crucial for theactivation of antiviral immune responses by patrolling cytotoxic T cells. Toavoid T cell detection, the MHC I antigen presentation pathway is targetedby many DNA viruses. For example, various herpesviruses interfere withthe supply of peptides necessary for the assembly of MHC I by inhibitingthe Transporter associated with Antigen Processing (TAP). TAP is also atarget of the recently identified cowpox viral protein CPXV12. This 9kDatype II transmembrane protein inhibits TAP mediated peptide transportthrough an unidentified mechanism. Here, we investigated the mechanismof TAP inhibition and the protein domains responsible for this effect. WeREF O51Specificity and predictability of CD4+ T cell responses after tick borneencephalitis virus infection and vaccination are strongly influenced bystructural features of viral proteinsJulia SCHWAIGER 1 , Judith H. ABERLE 1 , Karin STIASNY 1 , BernhardKNAPP 2 , Wolfgang SCHREINER 2 , Gottfried FISCHER 3 , OndrejSCHEINOST 4 , Vaclav CHMELIK 5 , Franz X. HEINZ 11 Department of Virology, Medical University of Vienna, Vienna, AUS-TRIA; 2 Section of Biosimulation and Bioinformatics, Medical Universityof Vienna, Vienna, AUSTRIA; 3 Department of Blood Group Serology andTransfusion Medicine, Medical University of Vienna, Vienna, AUSTRIA;4 Laboratory of Molecular Biology and Genetics, Hospital Ceske Budejovice,Ceske Budejovice, CZECH REPUBLIC; 5 Department of InfectiousDiseases, Hospital Ceske Budejovice, Ceske Budejovice, CZECH REPU-BLICStrong antibody responses by B cells require direct interaction with CD4+T cells which recognize MHCII associated epitopes of proteins internalizedby the B cell after Ig receptor recognition. We determined the helperT cell response after tick borne encephalitis (TBE) virus infection andvaccination of humans by analyzing overlapping peptides of the structuralproteins (C – capsid, prM/M – precursor/membrane,E–envelope) which– since the whole virus particle is internalized by the B cell – can allVirologie, Vol 17, supplément 2, septembre 2013S59
5 th European Congress of Virologypotentially contribute to the formation of neutralizing antibodies directedto E.The specificity of CD4+ T cells was analyzed using an IL 2 ELISpot assayand these experimental results were compared with epitope predictions forthe HLA class II alleles (DR, DP, DQ) of each individual.Our results show that the CD4+ T cell response to peptides of the C proteinis overrepresented after both, infection and vaccination. Despite strongindividual variation, patterns of immunodominance were identified whichare linked to structural features of the proteins (e.g. alpha helices or betasheets). The correlation between predicted and experimentally determinedepitopes differed strongly between the structural proteins. As many as 80%of the experimental epitopes in C but only less than 40% in prM/M and Ewere predicted by algorithms.In conclusion, there is evidence that protein specific structural featureshave a strong influence on epitope usage and on the predictability of suchepitopes by computer algorithms.REF O52A new lentiviral vector tool to evaluate measles virus escape frominfection- or vaccine-induced antibodiesCamille LEVY, Fouzia AMIRACHE, Caroline COSTA, CeciliaFRECHA, Claude P. MULLER, Hasan KWEDER, Robin BUCKLAND,François-Loïc COSSET, Els VERHOEYENCIRI, EVIR team, 69007, Lyon, FRANCELive measles virus (MV) vaccines are currently used worldwide and arehighly successful but MV still causes 4% of all child deaths worldwide.Importantly, circulating MVs give rize to MV strains mutated in differentepitopes of the MV envelope glycoproteins (gps), which is underlined byreoccuring MV outbreaks in the last years. Thus the risk exists that thevirus acquires multiple mutations allowing it to escape from vaccination.To evaluate this risk we engineered a lentiviral vector (LV) displayingat its surface the MV envelope gps H and F (H/F-LVs). These H/F-LVsretained the same target cell specificity as MV for human T, B and dendriticcells. Since these H/F-LVs encode for GFP, their neutralization by MVantibodies is detected by reduction of % of GFP+ target cells. Indeed,insertion of mutations in the Noose and NE major epitopes of the Hgp inthe H/F-LVs confirmed escape from NE and Noose specific antibodies butnot from antibodies in sera from MV vaccinated donors.Other emerging strains such as the MV-D genotypes are less sensitive toMV antibodies induced by vaccination. We attributed this to epitope shieldingby an extra glycosylation site, D416N, present in these MV D-cladestrains since introduction of this mutation into the H/F-LVs revealed lessneutralization by MV-specific antibodies. Finally, when this glycosylationsite was introduced into the H/F-LVs already mutated for the major epitopes,escape from MV-antibody neutralization was increased. Thus, thisvector tool might allow epitope-monitoring, invaluable in the surveillanceof measles epidemics.REF O53Design of Single Round Infection Alphaviruses: New Approaches ofVaccine DevelopmentIlya FROLOV 1 , Dal Young KIM 1 , Svetlana ATASHEVA 1 , EryuWANG 2 , Scott WEAVER 2 , Elena FROLOVA 11 University of Alabama at Birmingham, Birmingham, USA; 2 Universityof Texas Medical Branch, Galveston, USAThe Alphavirus genus in the Togaviridae family contains a number ofhuman and animal pathogens. The importance of alphaviruses has beenstrongly underappreciated; however, recent epidemics of chikungunyavirus has raised their profile. In spite of a continuous public health threat,to date no licensed vaccines have been developed to any alphavirus infections.The currently available experimental live vaccines and inactivatedviruses suffer from traditional draw backs, such as reactogenicity or lowefficiency and short lived immune response. We have applied an accumulatedknowledge about the mechanism of alphavirus replication and proteinfunction in virus host interactions to introduce a number of new approachesin designing attenuated variants. The artificially designed alphavirusesare constructed from genes derived from different, geographically isolatedviruses. They lack the important contributors to viral pathogenesis:proteins functioning in inhibition of the innate immune response, causeonly a single round infection in vivo and do not induce detectable diseaseeven in immunocompromized animals. Nevertheless, these mutants closelymimic natural viral infection in terms of RNA replication, productionof viral proteins and release of viral particles. Such alphaviruses alsoinduce a highly efficient, protective immune response. An additionalimportant characteristic of the recombinant viruses is their inability toreplicate in mosquito vectors. These new approaches are applicable for theconstruction of alphaviruses with a programmed, irreversibly attenuatedphenotype.REF O54Respiratory vaccination with live attenuated measles virus: studiestowards identification of the optimal site of vaccine deliveryRik DE SWART 1 , Rory D. DE VRIES 1 , Linda J. RENNICK 2 , GeertVAN AMERONGEN 1 , Stephen MCQUAID 3 , Selma YÜKSEL 1 ,R.Joyce VERBURGH 1 , Martin LUDLOW 2 , Albert D.M.E.OSTERHAUS 1 , W. Paul DUPREX 21 Erasmus MC, dept. Viroscience, Rotterdam, THE NETHERLANDS;2 Boston University, dept. Microbiology, Boston, USA; 3 Queen’s Universityof Belfast, Tissue Pathology, Belfast, NORTHERN IRELANDThe standard route of measles virus (MV) vaccination is subcutaneousinjection, which is far from the natural route of wild type MV transmission.Programs evaluating alternative vaccination routes have been hampered bya lack of knowledge about the primary cells that should be targeted. Theaim of our study was to determine whether MV vaccination via the respiratoryroute should target the upper or lower respiratory tract (LRT). Wegenerated a recombinant virus based on the Edmonston Zagreb (EZ) strain,expressing enhanced green fluorescent protein (EGFP) from an additionaltranscription unit in position 3 of the genome. The virus was grownin MRC 5 cells and formulated with the same stabilizers and excipientsused in the MV EZ vaccine produced by the Serum Institute of India.Four groups of twelve macaques were immunized with a dose of 10ˆ4TCID50 rMV EZ EGFP(3) via different routes of administration: injection,intra tracheal inoculation, intra nasal instillation or aerosol inhalation.In each group six animals were euthanized at early time points, whereasthe other six were followed up to assess immunogenicity. Infected cellswere detected in the muscle, nose and lungs, but systemic MV replicationwas virtually absent. Macrophages and dendritic cells were the predominanttarget cells in all cases. Animals vaccinated via the respiratory routehad the highest specific serum antibody when the virus was delivered tothe LRT. This study sheds new light on the tropism of live attenuatedMV vaccine, and identifies the LRT as the optimal target for respiratorydelivery.S60 Virologie, Vol 17, supplément 2, septembre 2013
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Contents5 th European Congress of V
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i r o l o g i eList of Keynote Spea
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