The long-term efficacy of vaccines is dependent on immunological memory of T and B cells. Recent advances in CD4 CD45RO+ memory T cells have identified CD4+ CD45RO− stem cell-like memory cells (SCM) in murine and human T cells. The objectives of this investigation were to establish if SCM cells are induced by vaccination in the RV144 clinical trial. We report here that ALVAC/AIDSVAX B/E induced significant increase in CD4 SCM, with phenotypic expression of CD45RO− CD62L+ CCR7+ CD95+ SCM (P = 0.004). Characterisation of 2 SCM sub-types 28 weeks after vaccination revealed significant increase (P < 0.002) in cells expressing CD122 (the β chain of IL-2/IL-15 receptor), whereas SCM expressing CCR5 (HIV-1 co-receptor) were significantly decreased (P < 0.005). These inverse changes were also seen in CD4 CD45RO+ CCR7+ central but not in CD45RO+ CCR7- effector memory T cells. The CXCR4 expressing SCM or the placebo controls showed no change. Furthermore, recombinant IL-15 induced replication of SCM, and oxidative stress agents elicited membrane associated (ma) IL-15, which also induced significant proliferation of SCM. Importantly, both CD4+ CD45RO− SCM and CD4+ CD45RO+ CCR7+ central memory T cells can harbour latent HIV-1. The data suggest the paradigm that increase in CD4+ CD122+ SCM and central memory T cells will boost long-term memory and simultaneously decrease in HIV-1 binding of corresponding CCR5+ cells will reduce HIV-1 infectivity. The effect on latency of the 2 major cell subsets harbouring latent HIV-1 will be studied.