Impact of IL-21 on HIV Vaccine

IL-21 对 HIV 疫苗的影响

• 批准号: 6946970
• 负责人: Danuta B Kozbor
• 金额: $ 25.68万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6946970
• 关键词: AIDS vaccines; active immunization; cytokine; cytotoxic T lymphocyte; genetically modified animals; immunity; interleukin 15; laboratory mouse; vaccine development; vaccine evaluation; vaccinia virus; vector vaccine

DESCRIPTION (provided by applicant): Impact of IL-21 on HIV Vaccine IL-21 is the most recent member of the IL-2 cytokine family that is involved in regulating CD8+ T cell responses, antibody production as well as innate immunity. Using DNA plasmids encoding soluble wild-type and domain-modified Env trimers from the HIV-189.6 isolate and the Gag-pol fusion protein construct consisting of clusters of conserved cytotoxic T lymphocyte (CTL) epitopes, we compared the ability of IL-2-, IL-15-, and IL-21-encoded plasmid DNAs to induce protective immunity against challenge with recombinant vaccinia viruses (rVVs) expressing env, gag and pol gene products in a murine model. Our results demonstrated that IL-21, delivered together with the Env vaccine, had a greater ability than IL-2 and comparable to that of IL-15 to induce protective immunity against challenge with rVV expressing homologous gp!60, though complete eradication of the virus was achieved only in mice treated with both IL-21 and IL-15 at the time of immunization. The protection was associated with elevated levels of Env-specific CTL and NK cell activities in IL-21/IL-15-treated mice, which surpassed those induced by each cytokine alone. The isotype profile of Env-specific antibody responses demonstrated an increased level of IgG1 than IgG2 antibody in mice treated with IL-21 at the time of vaccination, however in mice treated simultaneously with IL-21 and IL-15, IgG1 and IgG2 antibodies were balanced and higher than those elicited by the Env vaccine only. The analysis of kinetics of IL-21-induced protection revealed further increases in the vaccine efficacy when IL-21 plasmid was delivered five days after immunization, consistent with the notion that IL-21 exposure to an immune system that has been primed with an antigen may lead to the optimal augmentation of specific immune responses. We hypothesize that specific combination of IL-21 and IL-15 genes would increase DNA vaccine potency compared with only one of these activities due to the ability of IL-21 to promote IL-15-induced clonal expansion, differentiation, and survival of viral-specific CD8+ T cells, and induce a balanced level of IgG1/IgG2 antibody subclasses. The following specific aims will be pursued: i) To establish the regimen of IL-15 and IL-21 delivery relative to Env and Gag-pol DNA immunizations to maximize the effector differentiation of vaccine-specific immune responses, ii) To determine mechanisms by which IL-21 and IL-15 enhance the induction of memory T cells that provide long-term protection, and iii) To test the effect of optimized cytokine delivery on mucosal immunization and protection against mucosal challenge with rVVs expressing env, gag, or pol gene products. These results may help to optimize AIDS vaccine by exploring novel approaches to maximize the adaptive and innate immune responses in HIV infection.

描述（由申请人提供）：IL-21 对 HIV 疫苗的影响 IL-21 是 IL-2 细胞因子家族的最新成员，参与调节 CD8+ T 细胞反应、抗体产生以及先天免疫。使用编码来自 HIV-189.6 分离株的可溶性野生型和结构域修饰的 Env 三聚体的 DNA 质粒和由保守的细胞毒性 T 淋巴细胞 (CTL) 表位簇组成的 Gag-pol 融合蛋白构建体，我们比较了 IL-2- 、IL-15 和 IL-21 编码的质粒 DNA 可诱导针对表达 env、gag 和 pol 基因产物的重组痘苗病毒 (rVV) 攻击的保护性免疫在小鼠模型中。我们的结果表明，与 Env 疫苗一起递送的 IL-21 比 IL-2 具有更强的能力，并且与 IL-15 相当，能够诱导针对表达同源 gp!60 的 rVV 攻击的保护性免疫，尽管完全根除仅在免疫时同时接受 IL-21 和 IL-15 治疗的小鼠中才获得病毒。这种保护作用与 IL-21/IL-15 治疗小鼠中 Env 特异性 CTL 和 NK 细胞活性水平的升高有关，超过了每种细胞因子单独诱导的水平。 Env 特异性抗体反应的同种型谱表明，在接种疫苗时用 IL-21 治疗的小鼠中，IgG1 抗体水平高于 IgG2 抗体，但在同时用 IL-21 和 IL-15 治疗的小鼠中，IgG1 和 IgG2 抗体水平升高。平衡且高于仅由 Env 疫苗引起的结果。 IL-21 诱导保护的动力学分析表明，当免疫后五天递送 IL-21 质粒时，疫苗功效进一步增加，这与 IL-21 暴露于已用抗原引发的免疫系统的观点一致可能会导致特异性免疫反应的最佳增强。我们假设，与仅其中一种活性相比，IL-21 和 IL-15 基因的特定组合将增加 DNA 疫苗的效力，因为 IL-21 能够促进 IL-15 诱导的病毒克隆扩增、分化和存活。 -特异性 CD8+ T 细胞，并诱导平衡水平的 IgG1/IgG2 抗体亚类。将追求以下具体目标：i) 建立与 Env 和 Gag-pol DNA 免疫相关的 IL-15 和 IL-21 递送方案，以最大限度地提高疫苗特异性免疫反应的效应器分化，ii) 通过以下方法确定机制：其中 IL-21 和 IL-15 增强记忆 T 细胞的诱导，从而提供长期保护，以及 iii) 为了测试优化的细胞因子递送对粘膜免疫和针对表达 env 的 rVV 的粘膜攻击的保护作用， gag 或 pol 基因产物。这些结果可能有助于通过探索新方法来最大化艾滋病毒感染中的适应性和先天免疫反应，从而优化艾滋病疫苗。