Protective Immune Responses Elicited by Deglycosylated Live-Attenuated Simian Immunodeficiency Virus 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. Two thirds of the vaccinees contained the chronic SIVsmE543-3 infection (controllers), whereas one third did not (noncontrollers). In this study, we investigated immune correlates of heterologous challenge control in rhesus macaques of Burmese origin. Because depletion of CD8 cells in the controllers by administration of anti-CD8α Ab 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 noncontrollers, before and after vaccination with deglycosylated SIV. It is well established that IL-15 signal transduction occurs through "-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 were 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.