Abstract CD8 T-cell sensitivity is crucial for optimum control of persistent viral infections, including HIV-1. The devastating HIV-1 pandemic may be countered by development of a cytotoxic T cell (CTL) based vaccine if qualities associated with protection can be defined at the molecular level. However, the heterogeneity of the total viral-specific CTL response confounds identification of protective correlates, and T-cell sensitivity is no exception and remains controversial. To address this we reduced the heterogeneity of the HIV-1 CTL response to single units, generating 19 CTL clones that recognise the same HIV-1 derived epitope restricted by HLA B*08. Correlation of functional assays directly with the ability of each clone to suppress HIV-1 replication in vitro, the so-called viral suppression assay, identified high functional avidity as a key quality for suppressive activity. Remarkably, four clones from this panel, isolated from one individual, a long-term non-progressor, all used an identical T-cell receptor (TCR) yet had distinct T-cell sensitivity and suppressive activity. Two of these clones were characterised in detail, and had distinct cytokine profiles, regulated by epigenetic mechanisms, and differential expression of a group of cell surface receptors with the potential to modulate the signalling threshold to antigen. This is the first evidence that avidity maturation in CD8 T cells with the same TCR affinity occurs in viral infections in man as reported in the mouse. Modulation of sensitivity in CD8 T cells is crucial for viral suppression. Funding UK Medical Research Council.