Cross-Reactivity to Mutated Viral Immune Targets Can Influence CD8+ T Cell Functionality: An Alternative Viral Adaptation Strategy

Loss of T cell immunogenicity due to mutations in virally encoded epitopes is a well-described adaptation strategy to limit host anti-viral immunity. However, the relevance of mutations within T cell epitopes that retain immune recognition and are beneficial for the virus is a less understood adaptation strategy. To understand this adaptation strategy, we utilized a single cell transcriptome approach to identify features of the HIV-specific T cell responses targeting non-adapted (NAE) and adapted (AE) forms of epitopes. T cell receptor (TCR) repertoire and transcriptome were obtained from antigen-specific CD8 T cells of chronically (n=8) and acutely (n=4) HIV-infected subjects identified by HLA-I (class I) tetramers loaded with either form of the epitope or by upregulation of activation markers following stimulation with peptides representing these forms. CD8 T cells were predominantly dual tetramer, confirming a large proportion of cross-reactive TCR clonotypes among NAE- and AE-only activated T cells. The transcriptomic profile of CD8 T cells was dependent on the autologous virus. Subjects whose virus encoded the NAE form of the epitope (and who transitioned to the AE form at a later timepoint) exhibited an effective immune response, as indicated by expression of transcripts associated with polyfunctionality, cytotoxicity and apoptosis (largely driven by the genes GZMB, IFNg, CCL3, CCL4 and CCL5). These data suggest that viral adaptation at a single amino acid residue can provide an alternative strategy for viral survival by modulating the transcriptome of CD8 T cells and potentially selecting for less effective T cell clones from the acute to chronic phase.