MINI-HIV VARIANTS AS LIVE-ATTENUATED VACCINE STRAIN

小型 HIV 变种作为减毒活疫苗株

• 批准号: 6078561
• 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/6078561
• 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：（改编自申请人摘要）我们提出了一种新颖的方法 致力于构建下一代安全、基因稳定的HIV-1 变体作为减毒活艾滋病疫苗。当前一代的HIV-1 缺失变体不是永久减毒的，因此是不安全的。我们将 利用优化的组织培养进化系统， 从一种高效复制的复杂逆转录病毒进化而来， 将蛋白质转化为一种简单的病毒， 高效复制。假设逆转录病毒的自然进化开始于 对于获得额外基因功能的更简单形式，我们建议 将进化的方向转向更简单的HIV-1变种。 例如，在试点进化实验中，我们成功地选择了 缺乏三个辅助基因的快速复制型HIV-1变体。序列 分析和重建实验应揭示“补偿性 回复突变病毒使用的“策略”。这些快速复制的变异体 用于另一轮基因删除和随后的进化， 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变异体， 最小数量的基因微型艾滋病毒作为疫苗的潜在用途 应变最初是由霍华德特明提出的，尽管他建议 完全不同的路线来产生这样的试剂。附加安全 这些治疗性病毒的特性，我们也将 削弱了病毒基因的基本结构这些综合方法应该 产生一种安全的微型HIV变异体，可用作减毒活疫苗 株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 潜在的和它们诱导保护性免疫反应的能力。