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

Abstract

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 gp140ΔCFIHXB2/89.6 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 Env121–129 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.

IL-15 Treatment during Acute Simian Immunodeficiency Virus (SIV) Infection Increases Viral Set Point and Accelerates Disease Progression despite the Induction of Stronger SIV-Specific CD8+ T Cell Responses

“…Several studies have shown the ability of IL-15 to enhance the activation, function, and proliferation of NK cells and CD8 ϩ T cells (18 -26), and to function as a chemoattractant for the homing of lymphocytes to peripheral lymph nodes (LN) 3 and inflamed tissue either directly (11,27,28) or indirectly by inducing IL-8 and MCP-1 by monocytes (29). IL-15 overexpression suppresses progression to murine acquired immunodeficiency syndrome in mice infected with LP-BM5 murine leukemia virus (30) and can act as a plasmid adjuvant (31)(32)(33). In vitro IL-15 enhances survival, inhibits CD95-induced apoptosis, and augments effector function of HIV-specific CD8 ϩ T cells (34,35).…”

Expression of Interleukin-15 and Interleukin-15Rα in Monocytes of HIV Type 1-Infected Patients with Different Courses of Disease Progression

“…17,18,38 On the basis of these findings, IL-15 can be considered to have adjuvant potential to support DNA-based anti-HIV vaccines. This cytokine enhances the cytolytic activity of anti-HIV-specific CD8 T cells and increases the production of IFNc in animal models, [23][24][25][26][27][28][29][30] and its use with anti-HIV vaccines is currently being tested in clinical trials (www.Clinicaltrials.gov). However, not all studies support the beneficial effect of IL-15.…”

“…Its application was shown to enhance the immune responses induced by DNA-based anti-HIV vaccines. In a murine model administration of IL-15 enhanced the cytolytic activity of anti-HIV-specific CD8 + T cells and the production of IFN-c, [23][24][25][26] and its administration with IL-15Ra boosts these responses to even higher levels. 27 Similar effects have also been observed in rhesus macaques vaccinated against simian immunodeficiency virus (SIV) [28][29][30] or when immunized with HIV DNA vaccine.…”

L’interleukine-21, une cytokine clé dans le contrôle du VIH et d’autres infections virales chroniques

“…Par conséquent, l'IL-21 joue un rôle important dans la réponse immune dans une situation de réinfection ou de réactivation de virus latents. Une étude in vivo a démontré que l'IL-21, seule ou en combinaison avec l'IL-15, est capable de réguler la réponse immunitaire contre la glycoprotéine d'enveloppe (Env) du VIH-1 [36]. L'IL-21 a permis d'établir une résis-tance soutenue à la réplication et à la transmission du virus.…”

“…Le traitement par l'IL-21 et l'IL-15 a augmenté les fonctions effectrices des cellules T CD8 + , permettant ainsi une protection efficace. De plus, ces deux cytokines sont capables d'accroître la cytotoxicité cellulaire dépendante des anticorps et la lyse induite par le complément ciblant des cellules exprimant les glycoprotéines d'enveloppes du VIH-1, suite à l'augmentation du niveau de production d'anticorps neutralisants spéci-fiques de ces protéines [36].…”