| Cytotoxic T-lymphocytes (CTL) are a critical component of antiviral immunity. The ability of CTL to respond to antigen is largely governed by the acidity of the CTL towards its recognized epitope, via interactions between the CCL T-cell receptor (TCR) and virally-derived peptide bound to the surface of major histocompatibility molecules (pMHC) on the infected cell surface. TCR:pMHC avidity has been shown to be highly influential in antiviral activity of CTL with higher avidity responses tending to result in greater control of viral replication. For this reason, many studies examining CTL efficacy have relied on measurements of CTL structural avidity (the physical strength of the TCR:pMHC interaction) or functional avidity (the sensitizing dose of exogenous antigen needed to achieve a CTL response) in order to gauge antiviral activity. However, avidity requirements for different epitopes in viral infections can vary widely, as epitope expression levels are influenced by protein expression levels, efficiency of proteasomal processing, and peptide transport to the ER. These factors are not taken into account in avidity measurements, and the precise relationship between CTL avidity and antiviral activity is not well characterized. Viral mutations may result in CTL escape, but the magnitude of decreased avidity to qualify as an escape mutation is unknown. These studies examine the relationship between avidity and antiviral efficacy in both primary CTL isolated from HIV-1-infected subjects and primary CD8 T cells transduced with an HIV-1-specific TCR. Narrow thresholds of avidity are observed, over which small changes in CTL avidity can have significant impacts on CTL antiviral efficacy. It is shown that commonly used methods to detect HIV-1-specific CTL responses (such as the ELISpot assay) are capable of detecting CTL responses to epitope variants from different viral clades, but that detection of clade-variants does not necessarily translate into CTL antiviral efficacy. Finally, these studies show that increased avidity of the TCR:pMHC interaction through TCR mutagenesis can allow TCR-transduced CD8 T cells to inhibit a greater breadth of HIV-1 strains expressing different epitope variants, and that the magnitude of increased avidity need not be large in some instances to allow for this increased breadth. |
