HIV ENVELOPE PEPTIDE BASED VACCINE IN SHIV RHESUS MODEL

SHIV 恒河猴模型中的 HIV 包膜肽疫苗

• 批准号: 6511214
• 负责人: Jagannadha K Sastry
• 金额: $ 35.64万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2004-01-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6511214
• 关键词: AIDS vaccines; HIV envelope protein gp160; Macaca mulatta; Vibrionaceae; autologous transplantation; bacterial toxins; cholera toxin; dendritic cells; disease /disorder model; enterotoxins; immunization; laboratory mouse; leukocyte count; mucosal immunity; nonhuman therapy evaluation; simian AIDSs; simian immunodeficiency virus; synthetic peptide; synthetic vaccines; vaccine development; vector vaccine

DESCRIPTION: (Adapted from Applicant's Abstract) We hypothesized earlier that an effective vaccination strategy against HIV-induced AIDS should focus on priming cell-mediated immunity (CMI) by employing a cocktail of highly conserved epitopes identified to be reactive with multiple MHC haplotypes. Our long-term goal is to formulate a synthetic peptide-based vaccine against HIV because it offers the advantage of being defined, safe and economical. To achieve this goal, we proposed an innovative approach that included employing autologous dendritic cells (DC) for presenting the peptide cocktail and inducing efficient CMI responses for control of infection and pathology by SHIV in a rhesus monkey model. The vaccine consisted of a mixture of six synthetic peptides corresponding to highly conserved regions in the HIV envelope protein gpl60 that we identified in our previous studies, in a series of animal models (murine, rhesus and chimpanzee) and samples from HIV infected people (including long-term nonprogressors), to be capable of inducing HIV-specific CMI responses. The SHIV-rhesus model is best suited for testing the protective efficacy of the peptide-cocktail because, SHIV, a chimeric virus comprised of HIV envelope and SIV core, induces AIDS-like disease in macaques, and thus provides the best alternative for testing HIV env-based vaccines and therapeutics. Our study design for the innovation HIV vaccine proposal involved immunizing rhesus monkeys initially with the peptides in Freund's adjuvant followed later by infusions of peptide-pulsed autologous DC that resulted in efficient induction of proliferative and CTL responses in the vaccinated animals. Importantly, upon challenge with SHIV KU -2, efficient clearance of virus infected cells in circulation and reduction in plasma infectivity were observed in all the vaccinated animals but not in the controls, despite uniform infection in all the monkeys initially. In one of the control monkeys this coincided with a precipitous drop in CD4+ cells to below 50 in three weeks, and signs of wasting by week 34, typical of AIDS. These results serve as proof of the principle for a peptide-based vaccine against HIV. Now, we propose to use the same six-peptide cocktail as a vaccine in combination with autologous DC, as sole adjuvant, for priming protective immunity in the SHIV-rhesus model. Additionally, we propose to adopt the SHIV-rhesus model to test the immunogenicity and efficacy of the six-conserved HIV env peptide cocktail for mucosal vaccination strategies employing adjuvants based on novel bacterial toxins that are modified to eliminate toxicity but retain adjuvant capacity. We obtained pilot data showing the effectiveness of mutated forms of cholera toxin and a hitherto untested cytotoxic enterotoxin from Aeromonos hydrophila, as model mucosal adjuvants for inducing HIV env-specific Th and CTL responses in mice. Finally, we propose to formulate a DNA vaccine, consisting of a cocktail of plasmids with mini-gene constructs encoding the six conserved HIV env peptides, and test immunogenicity and protective efficacy in the SHIV-rhesus model.

描述：（改编自申请人的摘要）我们之前假设， 预防艾滋病毒引起的艾滋病的有效疫苗接种战略应侧重于 通过使用高度免疫调节剂的混合物来引发细胞介导的免疫（CMI）。 保守表位被鉴定为与多种MHC单倍型反应。我们 长期目标是研制一种基于合成肽的艾滋病毒疫苗 因为它提供了明确、安全和经济的优点。到 为了实现这一目标，我们提出了一种创新的方法，包括采用 用于呈递所述肽混合物的自体树突细胞（DC），以及 通过SHIV诱导有效的CMI应答以控制感染和病理 在恒河猴模型中。疫苗由六种合成的 对应于HIV包膜蛋白中高度保守区域的肽 我们在之前的一系列动物模型研究中发现的gpl 60 （鼠类、恒河猴和黑猩猩）和来自HIV感染者（包括 长期无进展者），能够诱导HIV特异性CMI 应答SHIV-恒河猴模型最适合于测试保护性 因为SHIV是一种嵌合病毒， HIV包膜和SIV核心，在猕猴中诱导艾滋病样疾病， 为检测HIV env疫苗提供了最佳替代方案， 治疗学我们的研究设计为创新艾滋病毒疫苗的建议涉及 首先用弗氏佐剂中的肽免疫恒河猴 随后输注肽脉冲的自体DC， 在接种疫苗的小鼠中有效诱导增殖和CTL应答 动物重要的是，在用SHIV KU-2挑战后，有效清除 病毒感染循环中的细胞和血浆感染性的降低， 尽管一致，但在所有接种疫苗的动物中均观察到，但在对照组中未观察到 所有猴子的感染。在一只对照组猴子身上， 与CD 4+细胞在三周内急剧下降至50以下相吻合， 到第34周时出现消瘦症状，这是典型的艾滋病症状。这些结果证明了 基于肽的艾滋病疫苗的原理现在，我们建议使用 与自体DC组合的疫苗相同的六肽混合物， 作为唯一佐剂，用于在SHIV-恒河猴模型中引发保护性免疫。 此外，我们建议采用SHIV-rhesus模型来检验 六种保守HIV env肽混合物的免疫原性和效力， 使用基于新细菌的佐剂的粘膜疫苗接种策略 经过修饰以消除毒性但保留佐剂能力的毒素。我们 获得的试验数据显示了变异形式的霍乱毒素的有效性 和一种迄今为止未经测试的来自Aeromonos piglia的细胞毒性肠毒素， 诱导HIV env特异性Th和CTL应答的模型粘膜佐剂 小鼠最后，我们建议配制一种DNA疫苗， 含有编码六种保守HIV env基因的微型基因构建体的质粒 肽，并在SHIV-恒河猴中测试免疫原性和保护效力 模型