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VACCINE TO INDUCE NEUTRALIZATION OF PRIMARY HIV STRAINS

诱导 HIV 原发株中和的疫苗

基本信息

批准号：
2887877
负责人：
DAVID DAVIS
金额：
$ 15万
依托单位：
INSTITUTE OF TROPICAL MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-09-30 至 2000-09-29
项目状态：
已结题

项目摘要

DESCRIPTION (adapted from the applicant's abstract): The broad long-term objective is to develop a human immunodeficiency virus type 1 (HIV-1) recombinant gpl20 prime, peptide boost vaccination strategy using an immunogen, adjuvant and injection schedule, which would be acceptable for human use. The specific aim of the present project is to study the neutralizing and enhancing responses, assayed with laboratory and primary isolates of homologous and heterologous HIV-1 clade B isolates, in rhesus monkeys, rabbits and rats primed with recombinant HIV-1 SF2gpl20 immune stimulating complexes (ISCOM) formulations and boosted with synthetic peptides. The research design and methods will be as follows: A sensitive assay will be developed for monitoring neutralizing and enhancing antibody against the homologous HIV-1 SF2 and heterologous primary clade B viruses (HIV-1 DH12, HIV-1 HAN2, for which stocks titrated in chimps exist) in already existing sera of successfully prime-boost vaccinated rhesus-monkeys. Non-phytohemagglutinin (PHA) stimulated peripheral blood mononuclear cells (PBMC), as well as enriched purified T4, CD3+, CD4+, HLA-DR+ non-PHA stimulated cells, will be evaluated as host cells in the neutralization assay. Enhancement of the monkey sera against primary clade B viruses (see above) will be monitored in enriched human macrophage cultures. In primed and boosted rabbits and rats, the effect of the following parameters on the production of neutralizing and/or enhancing antibodies against laboratory and primary HIV-1 clade B viruses will be studied: priming with HIV-2 SF2 gpl20 coupled to ISCOM either via their protein backbone or their carbohydrates; the effect of two prime boost regimens, prime with recombinant immunogen and boost with peptides versus prime with peptides and boost with recombinant immunogen; boosting with mimotopes which have shown high affinity to the human monoclonal antibody (mAb) immunoglogulin G (IgG) 1 bl2, which is known to neutralize primary HIV-1 isolates; the use of single copy 15 mer V2, V3 and CD4 peptide to boost versus shorter, overlapping peptides, presented as a multiple antigenic peptide. The prime-boost regimen, which induces in rabbits and rats the broadest cross-neutralization response and the lowest enhancement against the various primary HIV-1 clade B viruses, will be selected to go forward to challenge studies in rhesus monkeys with chimeric simian/human immunodeficiency virus (SHIV)-DH12 or SHIV HAN2. Ultimately, the most successful approach will be tested later on in chimpanzees.

描述（改编自申请人的摘要）：广泛的长期目的是开发一种人类免疫缺陷病毒1型（HIV-1）重组gp 120初免、肽加强免疫接种策略免疫原、佐剂和注射时间表，这对于人类使用。本项目的具体目标是研究中和和增强反应，用实验室和初级恒河猴中同源和异源HIV-1进化枝B分离株用重组HIV-1 SF 2gp 120免疫致敏的猴、兔和大鼠刺激复合物（ISCOM）制剂，并用合成的缩氨酸研究设计和方法如下：将开发用于监测中和和增强抗体的检测方法抗同源HIV-1 SF 2和异源主要进化枝B病毒（HIV-1 DH 12，HIV-1 HAN 2，在黑猩猩中存在滴定的库存），已经存在的成功初免-加强免疫的恒河猴的血清。非植物血凝素（PHA）刺激的外周血单个核细胞（PBMC）以及富集纯化的T4、CD 3+、CD 4+、HLA-DR+非PHA 刺激的细胞，将在中和中作为宿主细胞进行评价比色法增强猴血清抗原代进化枝B病毒（参见将在富集的人巨噬细胞培养物中监测。在致敏和加强的兔和大鼠，以下参数对产生抗实验室抗体的中和和/或增强抗体将研究主要HIV-1进化枝B病毒：用HIV-2 SF 2引发 gpl 20通过其蛋白质骨架或其蛋白质骨架与ISCOM偶联。碳水化合物;两种主要加强方案的效果，重组免疫原和用肽加强对比用肽初免，用重组免疫原加强免疫;用已显示对人单克隆抗体（mAb）免疫球蛋白G（IgG）具有高亲和力 1bl 2，已知其可中和原代HIV-1分离株; 单拷贝15聚体V2、V3和CD 4肽以加强与较短，重叠肽，作为多抗原肽呈现。预充-加强方案，其在兔和大鼠中诱导最广泛的交叉中和反应和最低增强对各种将选择原代HIV-1进化枝B病毒进行攻毒在恒河猴中进行的猴/人免疫缺陷病毒嵌合体研究（SIV）-DH 12或SIV HAN 2。最终，最成功的方法将是后来在黑猩猩身上进行了测试。