Protective immune responses elicited by deglycosylated live-attenuated SIV vaccine are associated with IL-15 effector functions

Deglycosylated, live-attenuated SIV vaccines elicited protective immune responses against heterologous SIVsmE543–3, which differs from the vaccine strain SIVmac239 to levels similar to those across HIV-1 clades. 2/3 of the vaccinees contained the chronic SIVsmE543–3 infection (controllers), whereas 1/3 did not (non-controllers). In this study, we investigated immune correlates of heterologous challenge control in rhesus macaques of Burmese origin. Since depletion of CD8+ cells in the controllers by administration of anti-CD8α antibody abrogated the control of viral replication, CD8+ cells were required for the protective immune response. However, classical SIV specific CD8+ T cells did not account for the protective immune response in all controllers. Instead, IL-15 responding CD8α+ cells, including CD8+ T and NK cells, were significantly higher in the controllers than those in the non-controllers, before and after vaccination with deglycosylated SIV. It is well established that IL-15 signal transduction occurs through “trans-presentation” in which IL-15 complexed with IL-15Rα on monocytes, macrophages and dendritic cells binds to IL-15 Rβ/γ expressed on CD8+ T and NK cells. Accordingly, levels of IL-15 stimulation was strongly affected by the depletion of monocytes from PBMCs, implying key roles of innate immune cells. These results suggest that intrinsic IL-15 responsiveness may dictate the outcome of protective responses and may lead to optimized formulations of future broadly protective HIV vaccines.