Interdisciplinary Analysis of HIV-Specific CD8+ T Cell Responses against Variant Epitopes Reveals Restricted TCR Promiscuity

Abstract

HIV-1–specific CTL responses play a key role in limiting viral replication. CTL responses are sensitive to viral escape mutations, which influence recognition of the virus. Although CTLs have been shown to recognize epitope variants, the extent of this cross-reactivity has not been quantitatively investigated in a genetically diverse cohort of HIV-1–infected patients. Using a novel bioinformatic binding prediction method, we aimed to explain the pattern of epitope-specific CTL responses based on the patients’ HLA genotype and autologous virus sequence quantitatively. Sequences covering predicted and tested HLA class I-restricted epitopes (peptides) within the HIV-Gag, Pol, and Nef regions were obtained from 26 study subjects resulting in 1492 patient-specific peptide pairs. Epitopes that were recognized in ELISPOT assays were found to be significantly more similar to the autologous virus than those that did not elicit a response. A single substitution in the presented epitope decreased the chance of a CTL response by 40%. The impact of sequence similarity on cross-recognition was confirmed by testing immune responses against multiple variants of six selected epitopes. Substitutions at central positions in the epitope were particularly likely to result in abrogation of recognition. In summary, the presented data demonstrate a highly restricted promiscuity of HIV-1–specific CTL in the recognition of variant epitopes. In addition, our results illustrate that bioinformatic prediction methods are useful to study the complex pattern of CTL responses exhibited by an HIV-1–infected patient cohort and for identification of optimal targets for novel therapeutic or vaccine approaches.

Functional Avidity and IL-2/Perforin Production Is Linked to the Emergence of Mutations within HLA-B*5701–Restricted Epitopes and HIV-1 Disease Progression

“…MHC I-restricted epitope escape has been shown to dramatically reduce the magnitude of the CD8 + T cell response (49). Previous studies have also found associations between higher magnitude of T cell responses and rapid escape (43, 50).…”

“…Epitope mutations that evade these immune responses can become fixed in the viral population as a result of the selective pressure from HIV-specific CD8 + T cells (1–5). Viral mutations can have an impact on peptide-MHC class I–T cell receptor (TCR) interactions (6, 7), binding of the peptide to the MHC class I molecules (5, 8–10), and the intracellular processing of the viral peptides (11–13). Several mutations completely abrogate an epitope-specific CD8+ T cell response while others are cross-recognized by the TCR of available T cell clones or induce recruitment of newly developed T cell clonotypes (14).…”

Increased Sequence Coverage through Combined Targeting of Variant and Conserved Epitopes Correlates with Control of HIV Replication

“…It is important to consider that epitope variant recognition has been widely reported in the context of progressive infection (28)(29)(30)(31). To date, variant recognition assessments have often focused on a limited number of epitopes and/or epitope variants, largely due to limited sample availability and the prohibitive cost of generating proteome-wide variant peptide sets.…”

Improved structural method for T-cell cross-reactivity prediction

“…Despite this variability, five epitope positions (p4-p8 -gates 1-3) and four MHC-I residues were consistently indicated as involved with TCR interactions, being present in more than 85% of these complexes. The P4-P6 positions of the epitope had already been observed as being directly involved in the stimulation of immunogenicity (Calis et al, 2012(Calis et al, , 2013Frankild et al, 2008;Hoof et al, 2010;Rudolph et al, 2006;Wucherpfennig et al, 2009). Several residues over the pMHC-I surface might participate in the interaction with the TCR, influencing the specific level of T-cell stimulation that will be triggered by each pMHC-I.…”