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-CD8 alpha 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 CD8 alpha(+) 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 "trans-presentation" in which IL-15 complexed with IL-15R alpha on monocytes, macrophages, and dendritic cells binds to IL-15 12 beta/gamma 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.