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: 6374418
• 负责人: Jagannadha K Sastry
• 金额: $ 49.14万
• 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 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6374418
• 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：（根据申请人的摘要改编）我们先前假设 针对HIV引起的艾滋病的有效疫苗接种策略应集中在 通过使用高度的鸡尾酒，启动细胞介导的免疫（CMI） 保守的表位被确定为多种MHC单倍型反应性。我们的 长期目标是制定基于合成肽的疫苗针对HIV 因为它提供了被定义​​，安全和经济的优势。到 实现这一目标，我们提出了一种创新的方法，包括采用 自体树突细胞（DC）用于呈现肽鸡尾酒和 通过SHIV诱导有效的CMI反应来控制感染和病理 在恒河猴模型中。疫苗由六个合成的混合物组成 对应于HIV包膜中高度保守区域的肽 我们在以前的研究中确定的GPL60在一系列动物模型中 （鼠，恒河和黑猩猩）以及来自艾滋病毒感染者的样本（包括 长期非探测器），能够诱导HIV特异性CMI 回答。 Shiv六型模型最适合测试保护性 肽 - 鸡尾酒的功效，因为Shiv是一种嵌合病毒 HIV包膜和SIV核心，诱导猕猴中的艾滋病样疾病，因此 提供了测试基于HIV Env的疫苗的最佳选择和 疗法。我们针对涉及创新HIV疫苗提案的研究设计 最初用弗林德佐剂中的肽免疫恒河猴 然后稍后注入肽脉冲自体DC，导致 在接种疫苗中有效诱导增生和CTL反应 动物。重要的是，在挑战Shiv Ku -2时，有效的清除率 病毒感染细胞流通和血浆感染性降低为 尽管均匀 最初在所有猴子中感染。在一个控制猴子中 与CD4+细胞中急剧下降到三周以下的50以下，并且 在第34周浪费的迹象，典型的艾滋病。这些结果是证明 针对HIV的基于肽的疫苗的原理。现在，我们建议使用 与自动DC结合使用的疫苗相同的六肽鸡尾酒， 作为唯一的佐剂，用于SHIV 6hesus模型中的启动保护性免疫。 此外，我们建议采用Shiv抗逆转模型来测试 六保守的HIV ENV肽鸡尾酒的免疫原性和功效 采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持辅助能力的毒素。我们 获得的试验数据显示了突变形式的霍乱毒素的有效性 和迄今未经测试的细胞毒性肠毒素来自Aeromonos Hydrophila，AS 模型粘膜佐剂，以诱导HIV ENV特异性TH和CTL反应 老鼠。最后，我们建议制定由鸡尾酒组成的DNA疫苗 具有编码六个保守的HIV Env的迷你基因构建体的质粒 肽，测试湿术的免疫原性和保护效果 模型。