Functional Antigen‐Specific CD8 T _SCM Responses Are Associated with Repeated Clearance of Hepatitis C Virus Infection

Natural clearance of hepatitis C virus (HCV) infection occurs in about 25% of primary infections, but offers only partial protective immunity against re-infections. This study hypothesised that long-lived polyfunctional HCV-specific CD8+ memory stem T cells (T_SCM) contribute to protective immunity in rare super-clearer subjects who repeatedly clear viraemia. Six super-clearers and four clearer-chronic subjects who resolved a primary infection but subsequently developed chronic infection were studied at multiple timepoints. The T_SCM population (CCR7+CD45RA+CD95+) was bulk sorted, labelled with CellTrace Violet (CTV), and stimulated in vitro for five days with cognate HCV peptide, IL-2/IL-15, and autologous PBMCs. Functionality of the expanded HCV-specific T_SCM was assessed via the proliferation, multi-potency, and stemness indices. Total HCV-specific CD8+ T cells from super-clearers exhibited enhanced proliferative recall capability compared with clearer-chronics. Furthermore, super-clearers exhibited higher HCV-T_SCM frequencies post-expansion (22.35 ± 34.35 vs. 2.41 ± 9.83; p = 0.0066). Notably, HCV-T_SCM in clearer-chronics had 'stemness' indices of zero in samples before the re-infection (i.e., no ability to generate T_SCM as progeny), whereas super-clearers consistently retained this key functional property. These findings suggest that the maintenance of self-renewing HCV-specific T_SCM may underpin long-term protective immunity against re-infection and could inform vaccine design strategies targeting durable cellular memory.