A human cytomegalovirus-based immunotherapy for HIV-1

描述：该项目的最终目标是开发一种针对人类免疫缺陷病毒(HIV)-1的免疫疗法，其基础是一种基于传播缺陷巨细胞病毒(CMV)的疫苗，该疫苗表达为最大限度覆盖B分支表位而设计的“定制”抗原。在非人灵长类动物模型中，恒河猴巨细胞病毒载体疫苗对强毒猴免疫缺陷病毒(SIV)表现出前所未有的保护作用。在最初感染后，SI最终从受保护的动物中清除，这表明CMV载体可以对受感染的个体提供治疗效果。巨细胞病毒载体在多个方面是独一无二的：即使载体在体内传播不足，它们也可以诱导和维持高水平的循环和组织驻留的效应记忆T细胞。此外，在缺乏控制T细胞启动的病毒基因产物的情况下，CMV载体诱导T细胞产生包括MHC-II限制性CD8+T细胞在内的非传统表位。重要的是，CMV载体可以在CMV阳性宿主中重复使用，而不会失去免疫原性。HIV序列的多样性对HIV疫苗的设计提出了挑战。然而，与努力实现对艾滋病毒亚种的尽可能广泛覆盖的预防性疫苗不同，治疗性疫苗可以针对感染者的实际毒株进行量身定做。因此，在这项建议中，我们将测试这样一种假设：与非定制方法相比，从包含针对给定HIV分支的T细胞表位覆盖进行优化的HIV抗原的小型疫苗小组中选择的定制疫苗鸡尾酒在诱导“相关的”T细胞反应方面更好。我们将使用新的算法来设计定制的抗原，使表位匹配最大化，并将这些抗原插入到TomegaVax在该提案的第一阶段开发的新的人CMV载体骨干中。我们将使用最近开发的针对HCMV的NHP模型来监测针对特定HIV毒株的表位特异性T细胞反应。基于这些结果，我们将设计我们最终的疫苗鸡尾酒。为了促进在良好制造实践(GMP)下制造HCMV载体，我们将根据初步数据首次显示HCMV在以前用于生产无关病毒疫苗的细胞类型中生长，从而生成一个补充主细胞库。在这个项目完成后，我们将设计、表征和开发一种制造战略，以产生临床级别的HCMV/HIV载体产品。

DESCRIPTION: The ultimate goal of this project is to develop an immunotherapy for human immunodeficiency virus (HIV)-1 based on a spread-deficient cytomegalovirus (CMV)-derived vaccine expressing "tailored" antigens designed for maximal coverage of clade B epitopes. In non-human primate models, rhesus CMV-vectored vaccines demonstrated unprecedented protection against highly virulent simian immunodeficiency virus (SIV). After initial infection, SI was ultimately cleared from protected animals suggesting that CMV-vectors can provide a therapeutic effect in infected individuals. CMV vectors are unique in multiple aspects: they can induce and maintain high levels of circulating and tissue-resident effector memory T cells even when vectors are spread-deficient in vivo. Moreover, in the absence of viral gene products that control T cell priming, CMV vectors induce T cells to unconventional epitopes including MHC-II restricted CD8+ T cells. Importantly, CMV vectors can be used repeatedly and in CMV-positive hosts without loss of immunogenicity. HIV sequence diversity poses a challenge to HIV vaccine design. However, unlike prophylactic vaccines which strive to achieve the broadest possible coverage of HIV sub-species, therapeutic vaccines can be tailored towards the actual strains present in an infected individual. In this proposal, we will therefore test the hypothesis that a tailored vaccine cocktail selected from a small vaccine panel containing HIV antigens optimized for T cell epitope coverage of a given HIV clade are superior with respect to inducing "relevant" T cell responses as compared to non-tailored approaches. We will use novel algorithms to design tailored antigens that maximize epitope-matches and we will insert these antigens into a new human CMV-vector backbone developed at TomegaVax during phase I of this proposal. We will monitor epitope specific T cell responses against specific HIV-strains using a recently developed NHP model for HCMV. Based on these results, we will design our final vaccine cocktail. To facilitate manufacturing of HCMV vectors under good manufacturing practices (GMP) we will generate a complementing master cell bank based on preliminary data showing, for the first time, HCMV growth in a cell type previously used for the manufacturing of unrelated viral vaccines. Upon completion of this project, we will have a designed, characterized, and developed a manufacturing strategy to generate clinical grade HCMV/HIV vector products.