PROGRAMMING HIV IMMUNITY FOR BROADLY NEUTRALIZING ANTIBODIES BY VACCINATION

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 我们拨款提案的总体目标是评估自然艾滋病毒 在HIV感染过程中出现的病毒env序列可以用作 诱导广谱反应的抗艾滋病毒中和抗体的免疫原。这些环境 正在克隆的序列将来自艾滋病毒感染者，他们在很短的时间内(2-3年)产生了广泛和有效的抗艾滋病毒交叉中和抗体反应。在项目1中，我们将监测艾滋病毒感染者，以确定那些在感染后不久就产生广泛的交叉中和抗体反应的人，Towe将详细描述这些反应。我们将从这些患者的纵向样本中扩增病毒包膜，并与项目2合作：(1)我们将研究CD4+T细胞辅助反应及其与广泛的抗HIV中和抗体反应的发展和维持之间的关系；以及(2)从这些受试者中克隆中和抗体。本项目1中确定的环境病毒将在项目3中用作免疫原，以测试它们可以引发广泛的 动物体内的交叉中和抗体反应。该计划由Core提供支持 A(Stamatatos)开发蛋白质免疫原，核心B(L·皮克和M·阿克瑟姆) 提供非人类灵长类和猕猴T细胞分析方面的专业知识，以及 核心C(海格伍德)为整个计划提供行政支持和支持 生物统计学。我们已经成功地证明，通过定点突变重建为密码子优化基因的自然基因(使用 Robins-Kraznitz算法)来自肯尼亚的A亚型患者 当作为DNA疫苗接种时，在兔子中具有免疫原性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The overall goal of our grant proposal is to evaluate the possibility that natural HIV viral env sequences that emerge during the course of HIV infection, can be used as immunogens to elicit broadly-reactive anti-HIV neutralizing antibodies. These env sequences are being clonedwill be derived from HIV infected subjects who during a very short period of time (2-3 years) developed broad and potent anti-HIV cross-neutralizing antibody responses. In Project 1, we arewill monitoring HIV infected subjects to identify those that develop broad cross-neutralizing antibody responses shortly following infection and towe will characterize in detail these responses. We arewill amplifying viral env from longitudinal samples from these patients and in conjunction with Project 2 we are: (1) we will examininge what role the CD4+ T cell helper responses and their relationship tohave in the development and maintenance of broad anti-HIV neutralizing antibody responses; and (2) cloninge the neutralizing antibodies from these subjects. The Envs identified in this Project 1 will be used as immunogens in Project 3 to test the hypothesis that they can elicit broad cross-neutralizing antibody responses in animals. The Program is supported by Core A (Stamatatos) to develop protein immunogens, by Core B (L Picker and M Axthelm) to provide expertise in nonhuman primates and T cell analyses in macaques, and Core C (Haigwood) forto support the entire Program with administrative support and biostatistics. We have been successful in showing that the natural genes, reconstructed as codon-optimized genes by site-directed mutagenesis (using the Robins-Kraznitz algorithm) from a subtype A patient from Kenya are highly immunogenic in rabbits, when delivered as DNA vaccines.