HIV patients with poor immune recovery show exhausted CD4+ stem cell memory cells and impaired COVID-19 vaccine response.

Vaccination triggers both humoral and cellular immune responses, generating memory T cells that ensure long-term protection. Among these, stem cell-like memory T cells (TSCM) are crucial for durable immunity due to their self-renewal and multipotency. In people with HIV (PWHIV), vaccine-induced responses can be weakened by persistent immune dysfunction. In this study, we longitudinally analyzed T cell memory responses following mRNA-1273 vaccination in PWHIV. Individuals with incomplete immune reconstitution (CD4+ < 500 cells/μL, CD4/CD8 < 0.4) showed reduced frequencies of Spike-specific CD4+ TSCM, lower levels of TCF-1 and higher expression of immune checkpoint molecules. We identified a subset of PD-1+TIGIT+ CD4+ TSCM and TCM cells that phenotypically resemble CD8+ exhausted-like progenitors (TPEX) and are enriched in PWHIV with poor immune recovery. Modulation of the Wnt/mTORs pathway via GSK3β inhibition restored TCF-1 expression and partially rescued antigen responsiveness, highlighting a potential strategy to improve vaccine efficacy in PWHIV.