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Increased Level and Longevity of Protective Immune Responses Induced by DNA Vaccine Expressing the HIV-1 Env Glycoprotein when Combined with IL-21 and IL-15 Gene Delivery¹

Elizabeth Bolesta^*, Aleksandra Kowalczyk^*, Andrzej Wierzbicki^2,*, Cheryl Eppolito^*, Yutaro Kaneko, Masafumi Takiguchi, Leonidas Stamatatos, Protul A. Shrikant^* and Danuta Kozbor^3,*

^* Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263; Institute of Immunotherapy for Cancer, Kinki University, Osaka, Japan; Division of Viral Immunology, Center for AIDS Research, Kumamoto University, Kumamoto, Japan; and Seattle Biomedical Research Institute, Seattle, WA 98109

We investigated the ability of a plasmid-derived IL-21 delivered alone or in combination with the IL-15 gene to regulate immune responses to the HIV-1 envelope (Env) glycoprotein induced by DNA vaccination. Mice were injected with the gp140CFI_HXB2/89.6 vector expressing a modified Env glycoprotein with C-terminal mutations intended to mimic a fusion intermediate, in which the most divergent region encoding the variable V1, V2, and V3 domains of CXCR4-tropic HxB2 virus was replaced with the dual-tropic 89.6 viral strain. Using a recombinant vaccinia virus expressing 89.6 Env glycoprotein (vBD3) in a mouse challenge model, we observed that IL-21 plasmid produced sustained resistance to viral transmission when injected 5 days after DNA vaccination. Moreover, IL-21 in a synergistic manner with IL-15 expression vector augmented the vaccine-induced recall responses to the vBD3 challenge compared with those elicited by immunization in the presence of either cytokine alone. The synergistic combination of IL-21 and IL-15 plasmids promoted expansion of CD8⁺CD127⁺ memory T cell pools specific for a subdominant HLA-A2-restricted Env_121–129 epitope (KLTPLCVTL). Our results also show that coimmunization with IL-21 and IL-15 plasmid combination resulted in enhanced CD8⁺ T cell function that was partially independent of CD4⁺ T cell help in mediating protection against vBD3 challenge. Furthermore, the use of IL-21 and IL-15 genes was able to increase Ab-dependent cellular cytotoxicity and complement-dependent lysis of Env-expressing target cells through augmentation of Env-specific IgG Ab levels. These data indicate that the plasmid-delivered IL-21 and IL-15 can increase the magnitude of the response to DNA vaccines.

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