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Search Results: 1 - 10 of 32244 matches for " Antonio Lanzavecchia "
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Dissecting the human T and B cell response to pathogens
Antonio Lanzavecchia
Arthritis Research & Therapy , 2011, DOI: 10.1186/ar3404
The instructive role of dendritic cells on T-cell responses
Federica Sallusto, Antonio Lanzavecchia
Arthritis Research & Therapy , 2002, DOI: 10.1186/ar567
Abstract: DCs possess specialized features, such as pathogen recognition, antigen capturing and processing machinery, migratory capacity and costimulatory molecules, that allow them to act as the professional antigen presenting cells (APC) [1]. DCs represent the interface between the universe of foreign and tissue-specific antigens and T lymphocytes. They also play a role in all aspects of T-cell responses, from the deletion of self-reactive thymocytes to the generation of effector and memory cells, as well as the induction of peripheral tolerance.In this review, we shall discuss how DCs provide a qualitative and quantitative framework for T-cell antigen recognition. We shall first summarize the requirements for T-cell activation and differentiation in terms of concentration of peptide–MHC complexes, costimulatory molecules and cytokines. We shall then consider how DCs assemble these components and deliver them, as discrete short-lived packets, to the T-cell areas. Finally, we shall discuss how the nature of the DC maturation stimuli determines the density and quality of antigen-carrying DCs and, consequently, the magnitude and class of T-cell responses.The signals that lead to T-cell activation are generated at the level of the immunological synapse, a specialized area of contact between T cells and APC where adhesion molecules and TCRs segregate into distinct supramolecular complexes [2,3]. At the synapse, the TCRs are sequentially triggered by peptide–MHC complexes, a process that allows the signal to be sustained for as long as the synapse is in place [4,5]. Synapses are stable in the absence of disturbing influences, but they can be disrupted by cell division, by death of APC or by external influences, such as collagen or chemokines. T cells continuously search for antigen and can rapidly shift from one APC to another offering a higher level of stimulation. While the duration of TCR stimulation depends on the duration of the synapse, the intensity of signal that T cells
Studies on membrane topology, N-glycosylation and functionality of SARS-CoV membrane protein
Daniel Vo?, Susanne Pfefferle, Christian Drosten, Lea Stevermann, Elisabetta Traggiai, Antonio Lanzavecchia, Stephan Becker
Virology Journal , 2009, DOI: 10.1186/1743-422x-6-79
Abstract: Coronaviruses have a broad range of vertebrate hosts and usually cause mild respiratory diseases in humans and animals [1-3]. In March 2003 the world health organization issued a global alert about a severe partially fatal respiratory disease named severe acute respiratory syndrome (SARS). SARS originated in Southeast China, affected thousands and spread to many countries worldwide via international travel. Drastic quarantine measures and tight travel restrictions finally contained the SARS outbreak [4,5]. In parallel, the etiologic agent of the outbreak was identified with unprecedented speed and turned out to be a novel coronavirus with several distinguishing features to known coronaviruses [6-8]. The SARS outbreak showed drastically that coronaviruses can develop into highly pathogenic agents with the potential to threaten public health and global economy severely [9,10].The coronaviral membrane protein (M) is the most abundant protein in the viral envelope and fulfils pivotal functions in the viral life cycle. Besides mediating incorporation of the nucleocapsid into the newly formed virions, M recruits all other viral structural components to the ER-Golgi-intermediate compartment (ERGIC) where virus assembly and budding takes place [11-13]. While the topology of SARS-CoV M is yet unknown and in silico analyses of its topology revealed partially contradictory results (Fig. 1), previous publications showed that other coronaviral M proteins consist of three transmembrane domains with either an N-terminal ecto- and a C-terminal endodomain (Nexo-Cendo) or an Nexo-Cexo orientation [14-16].SARS-CoV M is N-glycosylated at asparagine residue at position 4 and accumulates at steady state in the Golgi complex [17]. Whether glycosylation of M plays a role in its intracellular distribution and assembly of viral particles is not known. Immunofluorescence analyses demonstrated that M is mainly retained in the ERGIC [17,18].In the present study we have investigated the topology
Rational Engineering of a Human Anti-Dengue Antibody through Experimentally Validated Computational Docking
Luca Simonelli, Mattia Pedotti, Martina Beltramello, Elsa Livoti, Luigi Calzolai, Federica Sallusto, Antonio Lanzavecchia, Luca Varani
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0055561
Abstract: Antibodies play an increasing pivotal role in both basic research and the biopharmaceutical sector, therefore technology for characterizing and improving their properties through rational engineering is desirable. This is a difficult task thought to require high-resolution x-ray structures, which are not always available. We, instead, use a combination of solution NMR epitope mapping and computational docking to investigate the structure of a human antibody in complex with the four Dengue virus serotypes. Analysis of the resulting models allows us to design several antibody mutants altering its properties in a predictable manner, changing its binding selectivity and ultimately improving its ability to neutralize the virus by up to 40 fold. The successful rational design of antibody mutants is a testament to the accuracy achievable by combining experimental NMR epitope mapping with computational docking and to the possibility of applying it to study antibody/pathogen interactions.
Therapeutic Efficacy of Antibodies Lacking FcγR against Lethal Dengue Virus Infection Is Due to Neutralizing Potency and Blocking of Enhancing Antibodies
Katherine L. Williams,Soila Sukupolvi-Petty,Martina Beltramello,Syd Johnson,Federica Sallusto,Antonio Lanzavecchia,Michael S. Diamond,Eva Harris
PLOS Pathogens , 2013, DOI: 10.1371/journal.ppat.1003157
Abstract: Dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS) are life-threatening complications following infection with one of the four serotypes of dengue virus (DENV). At present, no vaccine or antiviral therapies are available against dengue. Here, we characterized a panel of eight human or mouse-human chimeric monoclonal antibodies (MAbs) and their modified variants lacking effector function and dissected the mechanism by which some protect against antibody-enhanced lethal DENV infection. We found that neutralizing modified MAbs that recognize the fusion loop or the A strand epitopes on domains II and III of the envelope protein, respectively, act therapeutically by competing with and/or displacing enhancing antibodies. By analyzing these relationships, we developed a novel in vitro suppression-of-enhancement assay that predicts the ability of modified MAbs to act therapeutically against antibody-enhanced disease in vivo. These studies provide new insight into the biology of DENV pathogenesis and the requirements for antibodies to treat lethal DENV disease.
Antigenic Fingerprinting of H5N1 Avian Influenza Using Convalescent Sera and Monoclonal Antibodies Reveals Potential Vaccine and Diagnostic Targets
Surender Khurana,Amorsolo L. Suguitan Jr.,Yonaira Rivera,Cameron P. Simmons,Antonio Lanzavecchia,Federica Sallusto,Jody Manischewitz,Lisa R. King,Kanta Subbarao,Hana Golding
PLOS Medicine , 2009, DOI: 10.1371/journal.pmed.1000049
Abstract: Background Transmission of highly pathogenic avian H5N1 viruses from poultry to humans have raised fears of an impending influenza pandemic. Concerted efforts are underway to prepare effective vaccines and therapies including polyclonal or monoclonal antibodies against H5N1. Current efforts are hampered by the paucity of information on protective immune responses against avian influenza. Characterizing the B cell responses in convalescent individuals could help in the design of future vaccines and therapeutics. Methods and Findings To address this need, we generated whole-genome–fragment phage display libraries (GFPDL) expressing fragments of 15–350 amino acids covering all the proteins of A/Vietnam/1203/2004 (H5N1). These GFPDL were used to analyze neutralizing human monoclonal antibodies and sera of five individuals who had recovered from H5N1 infection. This approach led to the mapping of two broadly neutralizing human monoclonal antibodies with conformation-dependent epitopes. In H5N1 convalescent sera, we have identified several potentially protective H5N1-specific human antibody epitopes in H5 HA[(-10)-223], neuraminidase catalytic site, and M2 ectodomain. In addition, for the first time to our knowledge in humans, we identified strong reactivity against PB1-F2, a putative virulence factor, following H5N1 infection. Importantly, novel epitopes were identified, which were recognized by H5N1-convalescent sera but did not react with sera from control individuals (H5N1 na?ve, H1N1 or H3N2 seropositive). Conclusion This is the first study, to our knowledge, describing the complete antibody repertoire following H5N1 infection. Collectively, these data will contribute to rational vaccine design and new H5N1-specific serodiagnostic surveillance tools.
Characterization of Neutralizing Profiles in HIV-1 Infected Patients from whom the HJ16, HGN194 and HK20 mAbs were Obtained
Sunita S. Balla-Jhagjhoorsingh, Betty Willems, Liesbeth Heyndrickx, Leo Heyndrickx, Katleen Vereecken, Wouter Janssens, Michael S. Seaman, Davide Corti, Antonio Lanzavecchia, David Davis, Guido Vanham
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0025488
Abstract: Several new human monoclonal antibodies (mAbs) with a neutralizing potential across different subtypes have recently been described. Three mAbs, HJ16, HGN194 and HK20, were obtained from patients within the HIV-1 cohort of the Institute of Tropical Medicine (ITM). Our aim was to generate immunization antibodies equivalent to those seen in plasma. Here, we describe the selection and characterization of patient plasma and their mAbs, using a range of neutralization assays, including several peripheral blood mononuclear cell (PBMC) based assays and replicating primary viruses as well as cell line based assays and pseudoviruses (PV). The principal criterion for selection of patient plasma was the activity in an ‘extended incubation phase’ PBMC assay. Neutralizing Abs, derived from their memory B cells, were then selected by ELISA with envelope proteins as solid phase. MAbs were subsequently tested in a high-throughput HOS-PV assay to assess functional neutralization. The present study indicates that the strong profiles in the patients' plasma were not solely due to antibodies represented by the newly isolated mAbs. Although results from the various assays were divergent, they by and large indicate that neutralizing Abs to other epitopes of the HIV-1 envelope are present in the plasma and synergy between Abs may be important. Thus, the spectrum of the obtained mAbs does not cover the range of cross-reactivity seen in plasma in these carefully selected patients irrespective of which neutralization assay is used. Nevertheless, these mAbs are relevant for immunogen discovery because they bind to the recombinant glycoproteins to which the immune response needs to be targeted in vivo. Our observations illustrate the remaining challenges required for successful immunogen design and development.
Immunogenetic Mechanisms Driving Norovirus GII.4 Antigenic Variation
Lisa C. Lindesmith equal contributor,Martina Beltramello equal contributor,Eric F. Donaldson,Davide Corti,Jesica Swanstrom,Kari Debbink,Antonio Lanzavecchia,Ralph S. Baric
PLOS Pathogens , 2012, DOI: 10.1371/journal.ppat.1002705
Abstract: Noroviruses are the principal cause of epidemic gastroenteritis worldwide with GII.4 strains accounting for 80% of infections. The major capsid protein of GII.4 strains is evolving rapidly, resulting in new epidemic strains with altered antigenic potentials. To test if antigenic drift may contribute to GII.4 persistence, human memory B cells were immortalized and the resulting human monoclonal antibodies (mAbs) characterized for reactivity to a panel of time-ordered GII.4 virus-like particles (VLPs). Reflecting the complex exposure history of the volunteer, human anti-GII.4 mAbs grouped into three VLP reactivity patterns; ancestral (1987–1997), contemporary (2004–2009), and broad (1987–2009). NVB 114 reacted exclusively to the earliest GII.4 VLPs by EIA and blockade. NVB 97 specifically bound and blocked only contemporary GII.4 VLPs, while NBV 111 and 43.9 exclusively reacted with and blocked variants of the GII.4.2006 Minerva strain. Three mAbs had broad GII.4 reactivity. Two, NVB 37.10 and 61.3, also detected other genogroup II VLPs by EIA but did not block any VLP interactions with carbohydrate ligands. NVB 71.4 cross-neutralized the panel of time-ordered GII.4 VLPs, as measured by VLP-carbohydrate blockade assays. Using mutant VLPs designed to alter predicted antigenic epitopes, two evolving, GII.4-specific, blockade epitopes were mapped. Amino acids 294–298 and 368–372 were required for binding NVB 114, 111 and 43.9 mAbs. Amino acids 393–395 were essential for binding NVB 97, supporting earlier correlations between antibody blockade escape and carbohydrate binding variation. These data inform VLP vaccine design, provide a strategy for expanding the cross-blockade potential of chimeric VLP vaccines, and identify an antibody with broadly neutralizing therapeutic potential for the treatment of human disease. Moreover, these data support the hypothesis that GII.4 norovirus evolution is heavily influenced by antigenic variation of neutralizing epitopes and consequently, antibody-driven receptor switching; thus, protective herd immunity is a driving force in norovirus molecular evolution.
Fetal Human Cytomegalovirus Transmission Correlates with Delayed Maternal Antibodies to gH/gL/pUL128-130-131 Complex during Primary Infection
Daniele Lilleri, Anna Kabanova, Maria Grazia Revello, Elena Percivalle, Antonella Sarasini, Emilia Genini, Federica Sallusto, Antonio Lanzavecchia, Davide Corti, Giuseppe Gerna
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0059863
Abstract: Primary human cytomegalovirus (HCMV) infections during pregnancy are associated with a high risk of virus transmission to the fetus. To identify correlates of intrauterine HCMV transmission, serial serum samples from HCMV transmitter and non-transmitter pregnant women with primary HCMV infection were analyzed for the presence of neutralizing antibodies against different glycoproteins and glycoprotein complexes, which are known to mediate entry into distinct types of host cells. Neutralizing activity was detected in the sera early after primary infection; absorption with a soluble pentameric complex formed by gH/gL/pUL128-131, but not with gH/gL dimer or with gB, abolished the capacity of sera to neutralize infection of epithelial cells. Importantly, an early, high antibody response to pentamer antigenic sites was associated with a significantly reduced risk of HCMV transmission to the fetus. This association is consistent with the high in vitro inhibition of HCMV infection of epithelial/endothelial cells as well as cell-to-cell spreading and virus transfer to leukocytes by anti-pentamer antibodies. Taken together, these findings indicate that the HCMV pentamer complex is a major target of the antibody-mediated maternal immunity.
Crystal Structure and Size-Dependent Neutralization Properties of HK20, a Human Monoclonal Antibody Binding to the Highly Conserved Heptad Repeat 1 of gp41
Charles Sabin equal contributor,Davide Corti equal contributor,Victor Buzon equal contributor,Mike S. Seaman,David Lutje Hulsik,Andreas Hinz,Fabrizia Vanzetta,Gloria Agatic,Chiara Silacci,Lara Mainetti,Gabriella Scarlatti,Federica Sallusto,Robin Weiss,Antonio Lanzavecchia,Winfried Weissenhorn
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1001195
Abstract: The human monoclonal antibody (mAb) HK20 neutralizes a broad spectrum of primary HIV-1 isolates by targeting the highly conserved heptad repeat 1 (HR1) of gp41, which is transiently exposed during HIV-1 entry. Here we present the crystal structure of the HK20 Fab in complex with a gp41 mimetic 5-Helix at 2.3 ? resolution. HK20 employs its heavy chain CDR H2 and H3 loops to bind into a conserved hydrophobic HR1 pocket that is occupied by HR2 residues in the gp41 post fusion conformation. Compared to the previously described HR1-specific mAb D5, HK20 approaches its epitope with a different angle which might favor epitope access and thus contribute to its higher neutralization breadth and potency. Comparison of the neutralization activities of HK20 IgG, Fab and scFv employing both single cycle and multiple cycle neutralization assays revealed much higher potencies for the smaller Fab and scFv over IgG, implying that the target site is difficult to access for complete antibodies. Nevertheless, two thirds of sera from HIV-1 infected individuals contain significant titers of HK20-inhibiting antibodies. The breadth of neutralization of primary isolates across all clades, the higher potencies for C-clade viruses and the targeting of a distinct site as compared to the fusion inhibitor T-20 demonstrate the potential of HK20 scFv as a therapeutic tool.
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