Increased Cytotoxic T-Lymphocyte Epitope Variant Cross-Recognition and Functional Avidity Are Associated with Hepatitis C Virus Clearance

Abstract

Hepatitis C virus (HCV) clearance has been associated with reduced viral evolution in targeted cytotoxic T-lymphocyte (CTL) epitopes, suggesting that HCV clearers may mount CTL responses with a superior ability to recognize epitope variants and prevent viral immune escape. Here, 40 HCV-infected subjects were tested with 406 10-mer peptides covering the vast majority of the sequence diversity spanning a 197-residue region of the NS3 protein. HCV clearers mounted significantly broader CTL responses of higher functional avidity and with wider variant cross-recognition capacity than nonclearers. These observations have important implications for vaccine approaches that may need to induce high-avidity responses in vivo.

Selection of high-avidity CD8 T cells correlates with control of hepatitis C virus infection

“…Although an in-depth analysis of liver-derived HCV-specific T cells would be required to directly address this issue, the assumption that high-avidity T cells are enriched in patients having recovered from HCV infection would better fit with studies reporting a correlation between selection of high-avidity T cells and clearance of several other viral infections. 25,26 This is also in agreement with a recent report suggesting higher functional avidity of NS3-specific T cells derived from recovered donors than chronically infected patients, 27 although this study did not allow direct comparison of CTL responses recognizing the very same pMHC complex nor a direct evaluation of TCR/ pMHC-avidity.…”

TCR-ligand dissociation rate is a robust and stable biomarker of CD8+ T cell potency

“…T cell functional avidity, which measures in vitro T cell responses when exposed to increasing antigen concentrations, has been largely associated with the control of viral (1)(2)(3) or tumor (4,5) load in animal models. In accordance with these observations, several findings in patients with HIV (6,7) or hepatitis C (8,9) infections further showed the key role of CD8 + T cells of high functional avidity in efficient viral control and clearance. Yet, others have challenged the functional superiority of such high-avidity cells, which may be prone to increased activation-induced cell death, senescence, or exhaustion (reviewed in ref.…”

Virological, Immune and Host genetics Markers in the Control of HIV Infection

“…In particular, proliferative capacity with high perforin expression and secretion of multiple cytokines such as IFN-γ, IL-2, TNF-α, MIP-1b and/or CD107a surface expression after antigen contact characterize the responses seen in LTNP [119,120]. In addition to polyfunctionality, the avidity of virus-specific T-cell responses is also considered a potentially important measure of an effective immune response and has been shown in HCV infection, to be associated with viral clearance and higher levels of cross-variant recognition [121,122]. Thus, the quality of the CD8+ T-cell response to HIV serves as a better marker of controlled infection than the quantity (i.e.…”