STABILITY AND STRUCTURE OF GP 120 ON INACTIVATED HIV

描述：(改编自申请人的摘要)： 一种传统上成功的病毒疫苗方法， 灭活病毒(WIV)在世界范围内受到的关注相对较少 全面努力开发有效的艾滋病毒/艾滋病疫苗。早期的成功 SIV模型中的WIV与异种细胞抗原相混淆 从用于繁殖SIV的人类细胞系中提取。成长中的SIV 在异基因或自体猴子细胞中显示出部分保护作用 一些实验。在HIV中，只有一种灭活病毒产品(Salk/IRC 免疫基因)在人体上进行了测试，这种材料并不是“完整的” 灭活病毒，因为包膜糖蛋白已经完全 已删除。此外，这款产品正在作为一种治疗药物进行测试 而不是预防性免疫原。自从发表了使用HIV-1的WIV研究以来 是极其有限的，需要做更多的工作来评估 艾滋病毒/艾滋病疫苗概念。一个众所周知的技术挑战是 人类免疫缺陷病毒的发生与HIV-1包膜糖蛋白的趋向性有关 8gp 120)在浓缩过程中使病毒粒子“脱落”， 灭活和提纯。第二个潜在的问题是损失 在失活步骤期间GP 120的“天然”低聚结构 涉及蛋白质变性的物质(例如福尔马林)。最近的研究表明 重要的抗原表位可能在gp120从 从齐聚物到单体构象。拟议的研究将旨在 在识别和/或选择艾滋病毒-1变种时，代表所有 主要亚型(A-F)，表现出高GP 120稳定性的表型 在正常外周环境中可通过多个通道维持 血淋巴细胞或细胞系。从这些HIV-1变种开始 在HIV的制备中提供了显著的优势 完全抗原性，这可能是保护的关键。申请者 将评估几个优先针对以下目标的失活程序 核酸而不是蛋白质(例如补骨脂素-UV，β-丙内酯， 伽马辐射)，gp120的寡聚体构象。最后，他们会 评估几种WIV制剂在小动物中的免疫原性。 初步研究将集中在C亚型，这是最流行的 发展中国家的亚型。

DESCRIPTION: (Adapted from applicant's abstract): A traditionally successful approach to viral vaccines, the whole inactivated virus (WIV), has received relatively little attention in the overall effort to develop an effective HIV/AIDS vaccine. Early successes with WIV in the SIV model were confounded by xenogeneic cellular antigens derived from the human cell lines used to propagate the SIV. Growing SIV in allogeneic or autologous monkey cells has shown partial protection in some experiments. In HIV, only one inactivated virus product (the Salk/IRC Immunogen) has been tested in humans and this material is not "whole" inactivated virus since the envelope glycoprotein has been completely removed. Furthermore, this product is being tested as a therapeutic rather than a prophylactic immunogen. Since published studies of WIV using HIV-1 are extremely limited, a great deal more needs to be done to evaluate this HIV/AIDS vaccine concept. One well known technical challenge to the development of WIV is the propensity of the envelope glycoprotein of HIV-1 8gp 120) to "fall off" the virion during the process of concentration , inactivation, and purification. A second potential problem is the loss of the "native" oligomeric structure of the gp 120 during inactivation steps that involve protein denaturation (e.g. formalin). Recent studies suggest that important antigenic epitopes may be lost when gp120 is converted from oligomeric to monomeric conformation. The proposed studies will be aimed at the identification and/or selection of HIV-1 variants, representing all major subtypes (A-F), which express a phenotype of high gp 120 stability that can be maintained through multiple passages in normal peripheral blood lymphocytes or cell lines. Starting with such HIV-1 variants should provide a significant advantage in the preparation of HIV that retains full antigenicity which may be critical for protection. The applicants will assess several inactivation procedures that preferentially target nucleic acid rather than protein (e.g. psoralen-UV, beta-propiolactone, gamma irradiation), oligomeric conformation of gp120. Finally, they will assess the immunogenicity of several WIV preparations in small animals. Initial studies will focus on subtype-C, one of the most prevalent subtypes in developing countries.