Cross-reactive HERV immunity to combat HIV-1 infection

交叉反应性 HERV 免疫对抗 HIV-1 感染

• 批准号: 7737332
• 负责人: DONALD E MOSIER
• 金额: $ 47.48万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-14 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7737332
• 关键词: AIDS/HIV problem; Antidotes; Antigens; Binding; CD8B1 gene; Cowpox virus; Data; Elements; Epigenetic Process; Genes; Genetic Transcription; Goals; HERVs; HIV; HIV-1; Human; Human Genome; Immune; Immune response; Immune system; Immunity; In Vitro; Indium; Infection; Knowledge; Length; Libraries; Long Terminal Repeats; Lymphoid Cell; Peptides; Proteins; Research Proposals; Sequence Homology; Smallpox; Stimulus; T memory cell; T-Lymphocyte; Transcript; Vaccination; Viral load measurement; Virus; base; combat; cross reactivity; genetic linkage; novel; prevent; promoter; response; small molecule; small molecule libraries; transmission process

DESCRIPTION (provided by applicant): In this proposal, we plan to elicit protective immunity to HIV-1 by activating the expression of human endogenous retrovirus (HERV) elements that encode proteins that share sufficient sequence homology to engender cross-reactive immunity. The use of normally silent endogenous genes as internal immunogens is based on recent data showing cross-reactivity between HERV and HIV-1 peptides and provocative genetic linkage between HERV loci in the human genome and control of HIV-1 virus load. Transcription from most HERV loci has been silenced by epigenetic changes to the long terminal repeat (LTR) region, and the goal of this project is to reverse this epigenetic silencing and promote the expression in lymphoid cells of two HERV transcripts, the full length HERV-K102 and pol-related HERV HCP5. Expression of these HERV-encoded proteins will stimulate an immune response that will be demonstrated to cross-react with HIV-1 antigens. Initially we will use agents known to activate latent HIV-1 LTRs to see if they will activate the selected HERV LTRs. We will then characterize the epigenetic changes and promoter binding that distinguishes latent from activated HERV LTRs. Using this knowledge, we will move to a small molecule screen of a 300,000 compound library to identify agents capable of activating HERV LTRs but not HIV-1 LTRs. The end product will be an inexpensive, orally available small molecule that will promote expression of endogenous immunogens that will provide cross-reactive immune protection against HIV-1 acquisition. The ability of this approach to elicit a cross-reactive CD8 T cell response that is protective against HIV-1 infection will be validated in vitro. The screen will also produce small molecules capable of activating HIV-1 but not HERV LTRs for use in combating latent HIV-1 infection of memory T cells, as well as small molecules capable of repressing activated HERV LTRs, providing an antidote should HERV activation have any negative impacts. This novel research proposal will take advantage of the relatedness between virus-like elements in the human genome and the HIV/AIDS virus to stimulate immunity that will prevent or slow the transmission of the HIV/AIDS virus. The approach will be to awaken the normal silent human endogenous retrovirus elements with small molecules selected from a very large library of chemical compounds, which will then provide a stimulus to the human immune system. The result will be "cross-protective" immunity, as best exemplified by the eradication of smallpox by vaccination with the related cowpox virus.

描述（由申请人提供）：在本提案中，我们计划通过激活人内源性逆转录病毒（HERV）元件的表达来引发针对 HIV-1 的保护性免疫，这些元件编码具有足够序列同源性的蛋白质以产生交叉反应免疫。使用通常沉默的内源基因作为内部免疫原是基于最近的数据，这些数据显示 HERV 和 HIV-1 肽之间的交叉反应性以及人类基因组中 HERV 基因座与 HIV-1 病毒载量控制之间的激发性遗传联系。大多数 HERV 位点的转录已因长末端重复 (LTR) 区域的表观遗传变化而沉默，该项目的目标是逆转这种表观遗传沉默并促进两种 HERV 转录物（全长 HERV-K102 和 pol 相关的 HERV HCP5）在淋巴细胞中的表达。这些 HERV 编码蛋白的表达将刺激免疫反应，该反应将被证明与 HIV-1 抗原发生交叉反应。最初，我们将使用已知可激活潜在 HIV-1 LTR 的药物来观察它们是否会激活选定的 HERV LTR。然后，我们将描述表观遗传变化和启动子结合，以区分潜在的和激活的 HERV LTR。利用这些知识，我们将对 300,000 个化合物库进行小分子筛选，以确定能够激活 HERV LTR 但不能激活 HIV-1 LTR 的药物。最终产品将是一种廉价的口服小分子，可促进内源性免疫原的表达，从而提供针对 HIV-1 感染的交叉反应免疫保护。这种方法能够引发交叉反应性 CD8 T 细胞反应，从而预防 HIV-1 感染，这一能力将在体外得到验证。该筛选还将产生能够激活 HIV-1 但不能激活 HERV LTR 的小分子，用于对抗记忆 T 细胞的潜在 HIV-1 感染，以及能够抑制激活的 HERV LTR 的小分子，在 HERV 激活产生任何负面影响时提供解毒剂。这项新颖的研究计划将利用人类基因组中的病毒样元件与艾滋病毒/艾滋病病毒之间的相关性来刺激免疫力，从而预防或减缓艾滋病毒/艾滋病病毒的传播。该方法将利用从非常大的化合物库中选择的小分子来唤醒正常沉默的人类内源性逆转录病毒元件，然后这些小分子将为人类免疫系统提供刺激。结果将是“交叉保护”免疫，通过接种相关的牛痘病毒来消灭天花就是最好的例证。