Memory-like HCV-specific CD8+ T cells retain a molecular scar after cure of chronic HCV infection

In chronic hepatitis C virus (HCV) infection, exhausted HCV-specific CD8(+) T cells comprise memory-like and terminally exhausted subsets. However, little is known about the molecular profile and fate of these two subsets after the elimination of chronic antigen stimulation by direct-acting antiviral (DAA) therapy. Here, we report a progenitor-progeny relationship between memory-like and terminally exhausted HCV-specific CD8(+) T cells via an intermediate subset. Single-cell transcriptomics implicated that memory-like cells are maintained and terminally exhausted cells are lost after DAA-mediated cure, resulting in a memory polarization of the overall HCV-specific CD8(+) T cell response. However, an exhausted core signature of memory-like CD8(+) T cells was still detectable, including, to a smaller extent, in HCV-specific CD8(+) T cells targeting variant epitopes. These results identify a molecular signature of T cell exhaustion that is maintained as a chronic scar in HCV-specific CD8(+) T cells even after the cessation of chronic antigen stimulation. Thimme and colleagues identify a molecular signature of T cell exhaustion resembling a 'chronic scar' that is imprinted in hepatitis C virus-specific CD8(+) T cells and cannot simply be reversed by viral clearance.