MINI-HIV VARIANTS AS LIVE-ATTENUATED VACCINE STRAIN

小型 HIV 变种作为减毒活疫苗株

• 批准号: 6374429
• 负责人: Benjamin Berkhout
• 金额: $ 15万
• 依托单位: UNIVERSITEIT VAN AMSTERDAM
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-15 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6374429
• 关键词: AIDS vaccines; attenuated microorganism; cell line; evolution; gene deletion mutation; human immunodeficiency virus 1; tissue /cell culture; vaccine development; virus replication

DESCRIPTION: (Adapted from Applicant's Abstract) We propose a novel approach towards the construction of a next generation of safe, genetically stable HIV-1 variants as live-attenuated AIDS vaccines. The current generation of HIV-1 deletion variants is not permanently attenuated, and therefore unsafe. We will use an optimized tissue culture evolution system to gradually force HIV-1 to evolve from an efficiently replicating, complex retrovirus that encodes nine proteins to a simple virus with three-to-five genes that is still able to replicate efficiently. Assuming that natural evolution of retroviruses started with the more simple forms that acquired additional gene functions, we propose to turn around the direction of evolution towards more simple HIV-1 variants. For instance, in pilot evolution experiments, we succeeded in selecting fast-replicating HIV-1 variants that lack three accessory genes. Sequence analysis and reconstruction experiments should reveal the "compensatory strategies" used by the revertant viruses. These fast-replicating variants will be used for another round of gene deletion and subsequent evolution to regain replication capacity. Thus, repeated cycles of gene deletion and evolutionary adaptation are proposed with the aim to obtain a replicating HIV-1 variant with a minimal number of genes. The potential use of mini-HIV versions as vaccine strain was proposed originally by Howard Temin, although he suggested a completely different route to generate such reagents. Additional safety features will be incorporated into these therapeutic viruses, and we will also attenuate the basic set of viral genes. These combined approaches should generate a safe mini-HIV variant that can be used as a live-attenuated vaccine strain. These viruses will await extensive replication tests to verify their genetic stability, followed by animal tests to screen for their pathogenic potential and their ability to induce a protective immune response.

描述：（改编自申请人的摘要）我们提出了一种新颖的方法 建造下一代安全，遗传稳定的HIV-1 变体作为实时艾滋病疫苗。当前一代HIV-1 删除变体不会被永久减弱，因此不安全。我们将 使用优化的组织培养进化系统逐渐将HIV-1迫使HIV-1 从编码九个的有效复制，复杂的逆转录病毒演变 具有三到五个基因的简单病毒的蛋白质，仍然能够 有效复制。假设逆转录病毒的自然进化开始 使用更简单的形式获得了其他基因功能，我们提出了 扭转进化方向向更简单的HIV-1变体。 例如，在飞行员进化实验中，我们成功选择了 快速复制的HIV-1变体缺乏三个附件基因。顺序 分析和重建实验应揭示“补偿性 策略“由恢复病毒使用。这些快速复制的变体将 用于另一轮基因缺失和随后的进化来恢复 复制能力。因此，基因缺失和进化的重复循环 提出了适应，目的是获得复制的HIV-1变体 最少的基因。迷你HIV版本作为疫苗的潜在用途 霍华德·特林（Howard Temin）最初提出了菌株，尽管他提出了 完全不同的途径生成此类试剂。附加安全 功能将纳入这些治疗病毒，我们也将 减轻基本的病毒基因集。这些合并的方法应该 生成一个安全的迷你HIV变体，可用作活体疫苗 拉紧。这些病毒将等待广泛的复制测试，以验证其 遗传稳定性，然后进行动物测试以筛查其致病性 潜力及其诱导保护性免疫反应的能力。