HIV Envelope Peptide-Based Vaccine in SHIV-Rhesus Model

SHIV-恒河猴模型中的 HIV 包膜肽疫苗

基本信息

批准号：
7008828
负责人：
Jagannadha K Sastry
金额：
$ 61.51万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-12-01 至 2008-11-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Vaccine development efforts against human immunodeficiency virus type 1 (HIV-1) are hindered by the high mutation rate of the virus, lack of clear understanding of the nature of the protective immunity, and limitations of available animal models for direct testing of HIV antigens for protection. We tested protective efficacy of a highly conserved HIV envelope peptide cocktail vaccine in Indian origin rhesus macaques by taking advantage of the chimeric virus SHIV, that expresses HIV envelope and causes AIDS in this model thereby allowing for direct testing of HIV vaccines based on envelope sequences. The HIV envelope peptides for the vaccine cocktail were selected through a series of studies in multiple animal models and in vitro studies with cells from HIV-infected long-term non-progressors, for broadly cross reactive T cell responses in the context of multiple MHC haplotypes. Since the peptide cocktail vaccine selectively primes cell-mediated immunity (CMI) in the absence of anti-HIV antibody production, it is possible to test protective efficacy of antiviral TH and CTL responses in this model. Three separate vaccine studies were conducted employing a total of 30 macaques for delivering the peptide cocktail vaccine with Freund's adjuvant and/or autologous dendritic cells (DC). Macaques immunized with ex vivo peptide cocktail-pulsed DC exhibited efficient induction of CMI, and upon challenge with pathogenic strains of SHIV (SHIV[ku2] and SHIV[89.6P]) showed significant reduction in viral set point accompanied by undetectable virus in the blood of majority of vaccinated animals. Importantly, no rebounds were observed in the vaccinated monkeys, some followed for over three years. These results strongly support the vaccine potential of the HIV envelope peptide cocktail and the efficiency of DC loaded ex vivo with peptides for priming protective CMI responses. We hypothesize that FIt3-ligand (FL) treatment followed by delivering the vaccine cocktail in the presence of CpG-containing oligodeoxynucleotides (ODN) will be an effective strategy for targeting the vaccine to DC in vivo. Further we propose that this strategy would entail the HIV envelope peptide cocktail to be a viable vaccine approach applicable to humans. We obtained preliminary data supporting FL-mediated mobilization of multiple subsets of DC with immunogenic properties in murine and primate studies. We will test whether FL treatment of macaques followed by vaccination with the HIV envelope peptide cocktail in CpG-ODN would be effective in priming strong CMI and protection against intravenous challenge using SHIV[KU2]. Since the major route of HIV infection is the mucosal epithelium and is predominantly by macrophage-tropic HIV strains, we will also test the effectiveness of the peptide cocktail targeted to DC in vivo using FL-treatment and CpG-ODN followed by mucosal challenge using SHIV[SF162P], (expressing macrophage-tropic HIV envelope). We will also test a mucosal vaccination strategy for delivering the peptide cocktail using a novel mutant cholera toxin (CT2*) that we observed to be a strong adjuvant for priming systemic and mucosal immune responses to several peptide antigens, including the HIV vaccine peptides in mice.

描述（由申请人提供）：针对人类免疫缺陷病毒1型（HIV-1）的疫苗开发工作受到病毒的高突变率的阻碍，对保护性免疫的性质缺乏明确的了解以及可直接测试HIV HIV抗原的可用动物模型的局限性。我们通过利用嵌合病毒SHIV来测试印度恒河猕猴中高度保守的HIV包络肽鸡尾酒疫苗的保护性疗效，该病毒SHIV表达了HIV信封，并在该模型中造成了帮助，从而允许基于信封序列的HIV疫苗直接测试HIV疫苗。通过在多种动物模型中的一系列研究以及与来自HIV感染的长期非培养剂的细胞进行体外研究，以在多种MHC单倍型的背景下对广泛的交叉反应性T细胞反应选择了疫苗鸡尾酒的HIV包膜肽。由于在没有抗HIV抗体产生的情况下，肽鸡尾酒疫苗有选择性地素细胞介导的免疫（CMI），因此可以在该模型中测试抗病毒TH和CTL反应的保护作用。进行了三项独立的疫苗研究，总共使用30杆猕猴，用弗林德的佐剂和/或自体树突状细胞（DC）输送肽鸡尾酒疫苗。用离体肽鸡尾酒脉冲DC免疫的猕猴表现出有效的CMI诱导，并且在与SHIV的致病菌株（SHIV [KU2]和SHIV [89.6P]）挑战时，在大多数疫苗接种动物的血液中伴随着无法检测的病毒，伴随着无法检测的病毒的病毒设定点显着降低。重要的是，在接种的猴子中没有观察到任何反弹，有些随后三年多。这些结果强烈支持HIV包膜肽鸡尾酒的疫苗电位，以及带有肽的直流载体的效率用于启动保护性CMI反应。我们假设FIT3-fimand（FL）处理，然后在含CPG的寡脱氧核苷酸（ODN）的情况下输送疫苗鸡尾酒将是将疫苗靶向疫苗到体内DC的有效策略。此外，我们建议该策略将需要艾滋病毒包络肽鸡尾酒是适用于人类的可行疫苗方法。我们获得了支持FL介导的多个DC亚群的初步数据，该数据在鼠和灵长类动物研究中具有免疫原性。我们将测试CPG-ODN中使用HIV包膜肽鸡尾酒接种猕猴的FL处理是否可以有效地启动强CMI并使用SHIV [KU2]来防止静脉内挑战。由于HIV感染的主要途径是粘膜上皮，主要由巨噬细胞 - 循环艾滋病毒菌株进行，因此我们还将使用FL-治疗和CPG-ODN和使用SHIV [SF162P]（表达MICCARP）的粘液挑战，然后使用cpg-odn，然后使用粘膜挑战来测试靶向直流的肽鸡尾酒的有效性。我们还将测试一种粘膜疫苗接种策略，该策略使用新型突变霍乱毒素（CT2*）传递肽鸡尾酒，我们观察到对几种启动的多种肽抗原的全身性和粘膜免疫反应是强的佐剂，包括小鼠中的HIV疫苗肽。