Antigen processing influences HIV-specific cytotoxic T lymphocyte immunodominance

Abstract

Although cytotoxic T lymphocytes (CTLs) in people infected with human immunodeficiency virus type 1 can potentially target multiple virus epitopes, the same few are recognized repeatedly. We show here that CTL immunodominance in regions of the human immunodeficiency virus type 1 group-associated antigen proteins p17 and p24 correlated with epitope abundance, which was strongly influenced by proteasomal digestion profiles, affinity for the transporter protein TAP, and trimming mediated by the endoplasmatic reticulum aminopeptidase ERAAP, and was moderately influenced by HLA affinity. Structural and functional analyses demonstrated that proteasomal cleavage 'preferences' modulated the number and length of epitope-containing peptides, thereby affecting the response avidity and clonality of T cells. Cleavage patterns were affected by both flanking and intraepitope CTL-escape mutations. Our analyses show that antigen processing shapes CTL response hierarchies and that viral evolution modifies cleavage patterns and suggest strategies for in vitro vaccine optimization.

MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape

“…In addition, there have been isolated reports of peptides with residues overhanging the C-terminal pocket of HLA-A*02:01 12,40 and H2-M3 41 . It was not clear, however, whether such overhangs could occur beyond the more buried N-terminal pocket.…”

“…The T-cell receptor (TCR) binds these bulged regions of the peptide whilst simultaneously contacting the HLA-I molecule. Isolated reports have described peptides that protrude at the C-terminus from the peptide-binding groove with the P-1 residue acting as an alternate C-terminal anchor, although the extent to which this represents a common occurrence remains unclear 11,12 . Such non-canonical HLA-I-peptide landscapes are important because they potentially form unique contact surfaces for TCR and killer immunoglobulin-like receptor (KIR) recognition with attendant implications for disease-relevant immune responses 12,13,14 .…”

CTL recognition of HIV‐1‐infected cells via cross‐recognition of multiple overlapping peptides from a single 11‐mer Pol sequence

“…Therefore, the results obtained in the present study suggest the following two possibilities: First, FV9 and FP10/FV11 peptides were presented on the surface of HIV-1-infected cells dominantly and subdominantly, respectively. A previous study showed that CD8 + T-cell response hierarchies to overlapping epitope peptides correlated with the predicted epitope abundance on the cell surface [19]. Therefore, although antigen-processing profiles were not analyzed in the present study, the FV9 peptide would be predominantly presented by HLA-B*54:01 in HIV-1-infected cells.…”

“…2012. 42: 2621-2631 Immunity to infection 2629 peptide (residues 263-270: KRWIILGL) more efficiently than it does the KK10 one [19], suggesting that KL8 as well as KK10 peptide might be presented by HLA-B27 for recognition by CD8 + T cells though the former is much effectively presented by the latter. In addition, two distinct HLA-B57-restricted p24 Gag-derived peptides, KI8 (residues 162-169: KAFSPEVI) and KF11 (residues 162-172: KAFSPEVIPMF), were reported to be recognized by distinct CD8 + T-cell clones from an HLA-B57 + HIV-1-infected individual [14].…”

“…HIV-1-specific CD8 + T cells recognize peptides derived from HIV-1 proteins presented by HLA class I molecules on HIV-1-infected cells, and effectively although not completely control the replication of HIV-1 [1,5,11,12]. Although any given HLA class I allele presents 8-mer to 11-mer peptides derived from different parts of HIV-1, it is also known that overlapping HIV-1 epitope Correspondence: Prof. Masafumi Takiguchi e-mail: masafumi@kumamoto-u.ac.jp peptides of different lengths from 8-mer to 11-mer from a given region can be presented by the same HLA class I molecule [13][14][15][16][17][18][19][20][21]. However, the role of the presentation of these overlapping peptides of different lengths in HIV-1-specific CD8 + T-cell recognition remains unclear.…”