Acute and chronic infections drive distinct trajectories in human memory CD4⁺ T cell formation

Virus-specific CD4⁺ T cells are essential for coordinating adaptive immunity during infection, but their differentiation and maintenance in chronic infection remain unclear. Using human hepatitis C virus (HCV) infection as a model, we assessed the determinants of virus-specific CD4⁺ T cell immunity in acute, spontaneously cleared, chronic, and therapeutically cured infections. During acute infection, multiple subsets of progenitor CD4⁺ T cells emerged, including subsets that are also found in chronic infection. In chronic infection, stem-like Bcl-2⁺ CD4⁺ T cells and T-bet⁺ effector CD4⁺ T cells existed in a progenitor/progeny relationship. Following therapy-mediated HCV cure, these cells retained their chronic signature but formed a stable memory pool that persisted for years and was distinct from HCV-specific CD4⁺ T cell memory after spontaneous clearance. Collectively, our findings highlight differences in CD4⁺ T cell fates that depend on infection outcomes and reveal common principles of CD4⁺ and exhausted CD8⁺ T cell maintenance during and after chronic infection.