Targeting virus entry and membrane fusion through specific peptide/MHC complexes using a high-affinity T-cell receptor

The T-cell receptor (TCR) determines the specificity of T-cell recognition by binding to peptide fragments of intracellular proteins presented at the cell surface in association with molecules of the major histocompatibility complex (MHC). Engagement of the TCR by its cognate peptide/MHC ligand, with appropriate co-stimulatory signals, leads to activation of T-cell effector functions. Here we show that the attachment proteins of attenuated measles viruses, engineered to display a high-affinity single-chain TCR (scTCR), can recognize and bind to specific peptide-MHC complexes and thereby mediate targeted virus-cell entry and cell-to-cell fusion. Using the 2C TCR and its peptide/MHC ligand (SIYRYYGL/mouse K(b)), we show that a scTCR grafted onto the measles virus H protein confers new specificity to virus entry and cell fusion. The efficiency of TCR-mediated virus entry was dependent on the number of peptide/MHC complexes expressed on the target cells, increasing progressively above densities higher than 2500 complexes per cell. This work introduces a new paradigm for targeting virus entry and membrane fusion by extending the repertoire of targets to specific peptide-MHC ligands and offering a novel quantitative readout for the cellular expression of peptide-MHC complexes.