ImmunomeBrowser analysis of B and T cell epitopes.

<p>R/T, number responded over number tested; RFscore, response frequency score; N-arm, N-terminal arm; NTD, N-terminal domain; CP, cytoplasmic, EC, extracellular; HBD, heparin binding domain; HRA/HRB, heptad repeats; DI, docking inhibition; Cys-noose, cysteine noose; bovine host*, natural infection in children/infants**, natural infection in adults***; bold indicates overlap.</p><p>ImmunomeBrowser analysis of B and T cell epitopes.</p

Analysis of Human RSV Immunity at the Molecular Level: Learning from the Past and Present

<div><p>Human RSV is one of the most prevalent viral pathogens of early childhood for which no vaccine is available. Herein we provide an analysis of RSV epitope data to examine its application to vaccine design and development. Our objective was to provide an overview of antigenic coverage, identify critical antibody and T cell determinants, and then analyze the cumulative RSV epitope data from the standpoint of functional responses using a combinational approach to characterize antigenic structure and epitope location. A review of the cumulative data revealed, not surprisingly, that the vast majority of epitopes have been defined for the two major surface antigens, F and G. Antibody and T cell determinants have been reported from multiple hosts, including those from human subjects following natural infection, however human data represent a minority of the data. A structural analysis of the major surface antigen, F, showed that the majority of epitopes defined for functional antibodies (neutralizing and/or protective) were either shown to bind pre-F or to be accessible in both pre- and post-F forms. This finding may have has implications for on-going vaccine design and development. These interpretations are in agreement with previous work and can be applied in the larger context of functional epitopes on the F protein. It is our hope that this work will provide the basis for further RSV-specific epitope discovery and investigation into the nature of antigen conformation in immunogenicity.</p></div

Epitopes that induce cytotoxicity in human CD8+ T cells.

<p>CP: cytoplasm; TM: transmembrane; EC: extracellular; RB: RNA binding</p><p>Epitopes that induce cytotoxicity in human CD8+ T cells.</p

Positional Bias of MHC Class I Restricted T-Cell Epitopes in Viral Antigens Is Likely due to a Bias in Conservation

<div><p>The immune system rapidly responds to intracellular infections by detecting MHC class I restricted T-cell epitopes presented on infected cells. It was originally thought that viral peptides are liberated during constitutive protein turnover, but this conflicts with the observation that viral epitopes are detected within minutes of their synthesis even when their source proteins exhibit half-lives of days. The DRiPs hypothesis proposes that epitopes derive from <b>D</b>efective <b>Ri</b>bosomal <b>P</b>roducts (DRiPs), rather than degradation of mature protein products. One potential source of DRiPs is premature translation termination. If this is a major source of DRiPs, this should be reflected in positional bias towards the N-terminus. By contrast, if downstream initiation is a major source of DRiPs, there should be positional bias towards the C-terminus. Here, we systematically assessed positional bias of epitopes in viral antigens, exploiting the large set of data available in the Immune Epitope Database and Analysis Resource. We show a statistically significant degree of positional skewing among epitopes; epitopes from both ends of antigens tend to be under-represented. Centric-skewing correlates with a bias towards class I binding peptides being over-represented in the middle, in parallel with a higher degree of evolutionary conservation.</p> </div

Linear B cell epitopes associated with virus neutralization or <i>in vivo</i> protection.

<p>PT, passive transfer</p><p>^X, shows cross-protection; PC, polyclonal; VN, virus neutralization; Prot, <i>in vivo</i> challenge/survival; NI, natural infection</p><p>^ch101F is a mouse-human chimeric of 101F; <b>Motavizumab</b> is also a mouse-human chimera; all others are mouse; A2, HRSV A2 strain; Long, HRSV long strain</p><p>Linear B cell epitopes associated with virus neutralization or <i>in vivo</i> protection.</p

Functional B cell epitopes mapped to F protein.

<p>Functional epitopes, comprising 115 total residues, are mapped to the RSV F protein (epitopes are shown in yellow). Three dimensional structures 4JHW (pre-fusion) and 3RKI (post-fusion) were selected to visualize the location of all residues using the IEDB Homology Mapping Tool. This considers all functional (neutralizing and/or protective) linear and conformational epitopes described to date in the literature.</p

RSA scores for F protein (pre and post) for all mAbs.

<p>Calculated relative solvent accessibility (RSA) scores for each residue comprising the indicated mAb epitope for pre-F and post-F conformations are shown side-by-side for those that differed on pre- and post-F structures. Exposed residues (>40%) are shown in red, buried residues (0–7%) are shown in blue and half-exposed residues (7–40%) are un-colored. Included (if known) is indication of binding preference on pre-F, post-F or both and historical antigen binding site. Abbreviations: MOTA, motavizumab; PALI, palivizumab.</p

MHC class I restricted T-cell epitopes retrieved from the Immune Epitope Database for viral species.

<p>For each organism, total number of tested peptides as well as numbers of those with positive and negative assay outcomes are shown. A total of 93 viruses were studied. For brevity, 20 viruses with the highest number of tested peptides are shown in the table.</p

Epitopes that induce IFNγ production from human CD8+ T cells.

<p>Role/Site abbreviations are included to indicate the role of the protein antigen in viral pathogenesis. VA: viral assembly; CP: cytoplasm; TM: transmembrane; EC: extracellular; HBD: heparin binding domain 184–198; RB: RNA binding; Inh IFN; inhibits IFN-mediated antiviral response; SS: signal sequence/N-terminus.</p><p>Epitopes that induce IFNγ production from human CD8+ T cells.</p

Positional biases of predicted binders for 12 HLA supertypes.

<p>For each supertype, 9-mer peptide binding predictions were carried out and ratios of probability masses of predicted ‘binders’ and ‘non-binders’ were calculated. Peptide binding predictions were made for alleles belonging to each supertype, using SMM^PMBEC method. All possible 9-mer peptides were generated from a set of viral proteins that contain at least one tested peptide from <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002884#pcbi-1002884-t001" target="_blank">Table 1</a>. Relationships between HLA molecules and supertypes are provided in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002884#pcbi.1002884-Sidney1" target="_blank">[11]</a>.</p