Patterns of Predicted T-Cell Epitopes Associated with Antigenic Drift in Influenza H3N2 Hemagglutinin

Abstract

Antigenic drift allowing escape from neutralizing antibodies is an important feature of transmission and survival of influenza viruses in host populations. Antigenic drift has been studied in particular detail for influenza A H3N2 and well defined antigenic clusters of this virus documented. We examine how host immunogenetics contributes to determination of the antibody spectrum, and hence the immune pressure bringing about antigenic drift. Using uTOPE™ bioinformatics analysis of predicted MHC binding, based on amino acid physical property principal components, we examined the binding affinity of all 9-mer and 15-mer peptides within the hemagglutinin 1 (HA1) of 447 H3N2 virus isolates to 35 MHC-I and 14 MHC-II alleles. We provide a comprehensive map of predicted MHC-I and MHC-II binding affinity for a broad array of HLA alleles for the H3N2 influenza HA1 protein. Each HLA allele exhibited a characteristic predicted binding pattern. Cluster analysis for each HLA allele shows that patterns based on predicted MHC binding mirror those described based on antibody binding. A single amino acid mutation or position displacement can result in a marked difference in MHC binding and hence potential T-helper function. We assessed the impact of individual amino acid changes in HA1 sequences between 10 virus isolates from 1968–2002, representative of antigenic clusters, to understand the changes in MHC binding over time. Gain and loss of predicted high affinity MHC-II binding sites with cluster transitions were documented. Predicted high affinity MHC-II binding sites were adjacent to antibody binding sites. We conclude that host MHC diversity may have a major determinant role in the antigenic drift of influenza A H3N2.

Recognition of Higher Order Patterns in Proteins: Immunologic Kernels

“…That would be consistent with experimental findings with synthetic peptides [14]. Natural experiments of immune escape tend to support the concept that local help may at least be the most important [23]. Asparagine endopeptidase clearly plays a role in release of longer peptides as a prerequisite to MHC-II binding [11].…”

“…MHC binding affinities and B-cell epitope contact points were predicted using techniques previously described and validated [21]–[23]. Probability of peptide cleavage likewise predicted based on discriminant equation ensembles derived by use of PCAA in conjunction with a probabilistic neural network for all possible amino acids in a scissile bond (P1-P1’) pair (see File S1).…”

“…In examining graphic plots of the location of predicted high affinity MHC binding proteins and B-cell epitopes in many proteins, we noted the frequent occurrence of “coincident epitope groups” in which multiple classes of epitope appear to overlap [21]–[23]. Recently, new proteomic approaches have provided a means to deduce large numbers of enzymatic cleavage patterns in a single experiment [24], [25].…”

Regions recognized on the light chain of botulinum neurotoxin type A by T lymphocytes of SJL and BALB/c mice primed with inactivated toxin

“…Table 4 lists immunodominant regions on the L and H chains in both strains that persisted during the course of the study. Shifts in the hierarchy of display of dominant and cryptic determinants (Viner et al, 1995;Homan and Bremel, 2011) may relate to local inflammatory states and to changes in antigen presenting cell population (Sercarz et al, 1993;Viner et al, 1995).…”

CD4+ T Cells Provide Intermolecular Help To Generate Robust Antibody Responses in Vaccinia Virus–Vaccinated Humans

“…Intramolecular help was also termed as cognate or homotypic help, which requires the antigenic determinants recognized by T and B cells to be covalently linked on the same antigen (11, 13). The model has received great attention for its academic and practical implications in studies of the nature of T cell help for antibody generation (26–32), in the strategy of CD4+ T cell epitope identification approaches that focus only on targets eliciting strong antibody responses (33–39), and in vaccine design studies that include proteins targeted strongly by CD4+ T cells (40–45). In spite of this interest and multiple citations, few studies have experimentally attempted to establish the linkage between CD4+ T cell and antibody responses in the response to large and complex antigens.…”