Preventative and therapeutic vaccines to HIV or SIV require effective innate immune responses and CD4+ memory stem cells The most successful smallpox vaccine demonstrates a broad spectrum of immune responses. We followed this principle and utilised oxidative stress agents to stimulate 4 anti-HIV immune pathways; homeostatic, type 1 IFN, inflammasome and HSP70-TLR4 in macaques and humans. We linked HSP70 to HIVgp140 and a stress agent to stimulate DC co-cultured with autologous PBMC. Three pathways were demonstrated by upregulation of IL-15, IFNαβ and IL-1β, and the corresponding receptors. Vaginal immunization in women with HIVp140 linked to HSP70 inhibited HIV-1 by innate and T cell immune responses and generated CD4+ memory stem cells. Specific antibodies were not induced but adding an enhancing agent elicited broadly neutralising HIV-1 antibodies. The mechanism of vaccination can now be expressed in terms of the 3 immune pathways and CD4+ memory stem cells.