Use of heterodimeric IL-15 in immune therapeutic regimens against HIV-1 or SIV infection (VAC8P.1048)

Abstract

Abstract Interleukin-15 (IL-15) promotes the growth of NK and memory CD8 T cells, which makes it an attractive candidate in immune therapeutic strategies to eradicate HIV-1 infection. We have shown that the relevant IL-15 molecule in vivo is the heterodimer (hetIL-15) composed of IL-15 chain and the so-named IL-15 Receptor alpha (IL-15Ra) chain. We developed expression vectors producing high levels of bioactive hetIL-15. We have also developed stable cell lines overproducing IL-15 heterodimers. SIV-infected and uninfected rhesus macaques were treated with these DNA plasmids by electroporation. In addition, SHIV-infected macaques received repeated subcutaneous injections of purified hetIL-15 protein or placebo. Electroporation of plasmid DNA resulted in increased levels of circulating IL-15, which typically peaked between day 4 and 5 in all the animals. Similarly, treatment with hetIL-15 protein gave sustained high cytokine plasma levels without any significant changes in plasma VL or any other adverse effects. In both studies, increased levels of IL-15 resulted in early decrease in the percentage of NK cells, probably linked to their mobilization out of the bloodstream, and preferential accumulation of CD8+ T lymphocytes with effector memory phenotype. In conclusion, the combination of CD8 effector cells expansion and lack of viral activation makes IL-15 an ideal component in immune therapeutic strategies for the treatment and potential eradication of HIV-1 infection.