An HLA-Directed Molecular and Bioinformatics Approach Identifies New HLA-A11 HIV-1 Subtype E Cytotoxic T Lymphocyte Epitopes in HIV-1-Infected Thais

Abstract

Only limited cytotoxic T lymphocyte (CTL) epitope mapping has been done in nonsubtype B HIV-infected persons. We used molecular immunogenetic tools to determine HIV-specific CTL responses in HIV-1 Env subtype E-infected female sex workers (FSWs) from northern Thailand, where more than 50% of the population is HLA-A11 positive. EpiMatrix, a computer-based T cell epitope prediction algorithm, and a manual editing approach were used to predict 77 possible HLA-A11 CTL epitopes in HIV-1, some of which were conserved between subtypes B and E. MHC binding of these peptides was determined in an HLA-A11 stabilization assay, and binding peptides were tested for CTL recognition in eight HLA-A11-positive FSWs. Subtype E versions of known HLA-A2 subtype B HIV epitopes were also tested in four HLA-A2 positive FSWs. CTL responses were detected in all HLA-A11-positive and in three of four HLA-A2-positive persons. Among the 12 FSWs responses to peptides were found to Pol in 9 (75%), Env in 7 (58%), Nef in 5 (42%), and Gag in 5 (42%), and to conserved epitopes in 8 (67%). To identify HLA-A11 CTL epitopes in the absence of prediction tools, it would have been necessary to test almost 3000 10-mer peptides. EpiMatrix and manual predictions reduced this number to 77, of which 26 were MHC binding and 12 were CTL epitopes. Six of these HLA-A11 CTL epitopes have not been previously reported and are located in RT, gp120, and gp41. This report of CTL responses in subtype E-infected individuals defines epitopes that may be useful in HIV pathogenesis or vaccine studies.

Broad Cross-Clade T-Cell Responses to Gag in Individuals Infected with Human Immunodeficiency Virus Type 1 Non-B Clades (A to G): Importance of HLA Anchor Residue Conservation

“…In addition, we could identify additional epitopes that are in part responsible for the cross-clade T-cell responses observed in our study by using HLA motif-finding algorithms. Although it is known that HLA motif prediction can miss in vivo-responsive CTL epitopes (23), a bioinformatics approach has proven to correlate with in vivo findings (13,21,45,58). In total, 25% (6/24) of the positive Gag pools in our study could be linked with previously documented cross-clade-responding epitopes in non-clade B-infected patients.…”

Extensive HLA class I allele promiscuity among viral CTL epitopes

“…Using these binding motifs, computational algorithms were developed that predicted a number of peptides derived from pathogens that would be capable of binding to given alleles. Subsequent experimental detection of immune responses to these predicted peptides and HLA binding studies validated the algorithms in many cases and provided further experimental evidence for the validity of allele-specific binding motifs [5][6][7][8][9].…”

Structures of HLA-A*1101 Complexed with Immunodominant Nonamer and Decamer HIV-1 Epitopes Clearly Reveal the Presence of a Middle, Secondary Anchor Residue

“…This knowledge is important for improving computer-based predictions of high-affinity HLA-A*1101-restricted CTL epitopes in viral-and tumor-associated proteins (48,49) and for understanding presentation of CTL epitopes by HLA-A*1101.…”