HSV Amplicon Vectors for HIV Vaccine Development

用于 HIV 疫苗开发的 HSV 扩增子载体

• 批准号: 6408835
• 负责人: Thomas G Evans
• 金额: $ 22.07万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-15 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6408835
• 关键词: Herpesviridae vaccine; MHC class I antigen; MHC class II antigen; antigen antibody reaction; biotechnology; cell line; cell mediated lymphocytolysis test; cellular immunity; cytotoxic T lymphocyte; drug delivery systems; drug design /synthesis /production; drug screening /evaluation; enzyme linked immunosorbent assay; gene expression; genetic mapping; genetically modified animals; helper T lymphocyte; herpes simplex virus 1; human immunodeficiency virus 1; humoral immunity; laboratory mouse; neutralizing antibody; transfection /expression vector; vaccine development; vector vaccine; western blottings

DESCRIPTION: (Provided by Applicant) The development of an effective prophylactic vaccine for HIV-1 will likely need an immunogen that can induce neutralizing antibody, and CD4 and CD8 T cell activity. Viral vector systems that infect cells and allow intracellular expression of HIV-1 gene products have the ability to activate T cells through MHC class I and II presentation. Herpes simplex virus type-1 (HSV-1) amplicons possess many of the desirable features of such a viral vector system. They are non-replicating, induce robust CD8+ T cell responses in mice, are easily manufactured, and infect a variety of antigen presenting cells, including dendritic cells. The HSV-1 amplicon can incorporate large segments of DNA, express more than one gene product, are not contaminated by helper virus, and are under development and evaluation as gene therapy tools. In initial experiments, HSV-1 amplicons expressing HIV-1 MN gp120 were shown capable of inducing interferon gamma-producing T cells at a number equivalent to that induced by live herpesvirus vectors, and far exceeding that of a modified vaccinia Ankara vector. In addition, the amplicons induced large anti-Env antibody responses. Building upon these observations, three specific aims are proposed. The first will be to construct amplicons which express codonoptimized clade C env, gag, and tat genes, and evaluate the protein expression from such vectors in vitro. In the second aim, the optimum route of parenteral and mucosal delivery, the dose and duration of immunity, and the effect of prior immunity to HSV will be evaluated. Lastly, the immune responses induced by the clade C amplicon will be evaluated in BALB/c and mapped in HLA-A2/human beta2 microglobulin transgenic mice. Overall, it is anticipated that these experiments will generate sufficient data to warrant moving the HSV-1 amplicon vaccine concept into non-human primate and human vaccine trials.

描述：（由申请人提供）开发一种有效的 HIV-1 预防性疫苗可能需要一种能够诱导 中和抗体以及 CD4 和 CD8 T 细胞活性。病毒载体系统 感染细胞并允许 HIV-1 基因产物在细胞内表达 具有通过 MHC I 类和 II 类呈递激活 T 细胞的能力。 单纯疱疹病毒 1 型 (HSV-1) 扩增子具有许多理想的特性 这种病毒载体系统的特征。它们是非复制的，具有鲁棒性 小鼠体内的 CD8+ T 细胞反应很容易制造，并且可以感染多种抗原呈递细胞，包括树突状细胞。 HSV-1 扩增子可以 包含大片段 DNA，表达不止一种基因产物，不是 被辅助病毒污染，正在作为基因进行开发和评估 治疗工具。 在最初的实验中，显示了表达 HIV-1 MN gp120 的 HSV-1 扩增子 能够诱导产生相当数量的干扰素 γ 的 T 细胞 与活疱疹病毒载体诱导的效果相比，远远超过了 改良痘苗安卡拉载体。此外，扩增子诱导了大 抗 Env 抗体反应。根据这些观察结果，提出了三项具体的 提出了目标。第一个是构建表达的扩增子 对 C 进化枝 env、gag 和 tat 基因进行密码子优化，并评估蛋白质 此类载体的体外表达。在第二个目标中，最优路径为 肠胃外和粘膜递送、免疫的剂量和持续时间以及 将评估先前对 HSV 免疫的效果。最后，免疫反应 由进化枝 C 扩增子诱导的扩增子将在 BALB/c 中进行评估并映射到 HLA-A2/人β2微球蛋白转基因小鼠。总体来说还是值得期待的 这些实验将产生足够的数据来保证移动 HSV-1 扩增子疫苗概念进入非人类灵长类动物和人类疫苗试验。