25 research outputs found
Intrapatient Escape in the A*0201-Restricted Epitope SLYNTVATL Drives Evolution of Human Immunodeficiency Virus Type 1 at the Population Level
The hypothesis that the intrapatient emergence of cytotoxic T-lymphocyte escape variants contributes to the evolution of human immunodeficiency virus type 1 at the population (interpatient) level was tested using the HLA-A*0201-restricted gag p17 epitope SLYNTVATL. Using a simple experimental design, we investigated the evolutionary processes operating within this epitope among patients while compensating for the confounding influence of intrapatient natural selection. Using this approach, we revealed a pattern of A*0201-driven escape within patients, followed by the sustained transmission of these escape variants among patients irrespective of their HLA type
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Immune selection for altered antigen processing leads to cytotoxic T lymphocyte escape in chronic HIV-1 infection.
Mutations within cytotoxic T lymphocyte (CTL) epitopes impair T cell recognition, but escape mutations arising in flanking regions that alter antigen processing have not been defined in natural human infections. In human histocompatibility leukocyte antigen (HLA)-B57+ HIV-infected persons, immune selection pressure leads to a mutation from alanine to proline at Gag residue 146 immediately preceding the NH2 terminus of a dominant HLA-B57-restricted epitope, ISPRTLNAW. Although N-extended wild-type or mutant peptides remained well-recognized, mutant virus-infected CD4 T cells failed to be recognized by the same CTL clones. The A146P mutation prevented NH2-terminal trimming of the optimal epitope by the endoplasmic reticulum aminopeptidase I. These results demonstrate that allele-associated sequence variation within the flanking region of CTL epitopes can alter antigen processing. Identifying such mutations is of major relevance in the construction of vaccine sequences
Mutually Exclusive T-Cell Receptor Induction and Differential Susceptibility to Human Immunodeficiency Virus Type 1 Mutational Escape Associated with a Two-Amino-Acid Difference between HLA Class I Subtypes
The relative contributions of HLA alleles and T-cell receptors (TCRs) to the prevention of mutational viral escape are unclear. Here, we examined human immunodeficiency virus type 1 (HIV-1)-specific CD8(+) T-cell responses restricted by two closely related HLA class I alleles, B*5701 and B*5703, that differ by two amino acids but are both associated with a dominant response to the same HIV-1 Gag epitope KF11 (KAFSPEVIPMF). When this epitope is presented by HLA-B*5701, it induces a TCR repertoire that is highly conserved among individuals, cross-recognizes viral epitope variants, and is rarely associated with mutational escape. In contrast, KF11 presented by HLA-B*5703 induces an entirely different, more heterogeneous TCR β-chain repertoire that fails to recognize specific KF11 escape variants which frequently arise in clade C-infected HLA-B*5703(+) individuals. These data show the influence of HLA allele subtypes on TCR selection and indicate that extensive TCR diversity is not a prerequisite to prevention of allowable viral mutations
Transmission pair information.
a<p>M: male; F: female.</p>b<p>D: donor, LR: virologically linked recipient.</p>c<p>Fiebig stage: Fiebig stage of the recipients at the time of enrollment into the IAVI protocol C early infection study, when plasma was first collected for viral sequence analysis.</p>d<p>pVL: Plasma viral loads for the recipients are shown at the time of screening prior to enrollment into the IAVI protocol C early infection study, when R880F was at Fiebig stage III and R463F at Fiebig stage IV. The plasma viral load in R463F at Fiebig stage V was 3,980,000 copies/ml. Plasma viral loads in the donors are shown at the timepoint when the recipients were at Fiebig stage III/IV.</p><p>Transmission pair information.</p
T cell response kinetics during acute and early HIV-1 infection.
<p>For both R880F (A) and R463F(B), individual peptide response magnitudes in an IFNγ ELISpot assay are shown as a percentage of the overall response. The insert shows the number of peptide responses detected and the total response magnitude (SFC/10<sup>6</sup> PBMCs) at each of the time points tested. The sequences of the peptides are shown in <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004565#ppat-1004565-t002" target="_blank">Table 2</a>.</p