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）：在此提案中，我们计划通过激活人体内源性逆转录病毒（HERV）元素的表达来引起对HIV-1的保护性免疫，这些元素编码蛋白质，这些蛋白质具有足够的序列同源性，以引起交叉反应性免疫。正常内源基因作为内部免疫原子的使用是基于最近的数据，显示了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病毒负荷的控制之间的挑衅性遗传联系。大多数HERV基因座的转录被长期重复（LTR）区域的表观遗传变化所沉默，该项目的目的是逆转这种表观遗传沉默，并促进两个HERV转录物的淋巴样细胞中的表达，即全长HERV-K102和POL相关的HERV HCP5。这些HERV编码的蛋白的表达将刺激免疫反应，该免疫反应将与HIV-1抗原交叉反应。最初，我们将使用已知的代理来激活潜在的HIV-1 LTR，以查看它们是否会激活所选的HERV LTR。然后，我们将表征表观遗传变化和启动子结合，从而区分潜在的HERV LTR。利用这些知识，我们将移至300,000个复合库的一个小分子屏幕，以识别能够激活HERV LTR而不是HIV-1 LTR的药物。最终产物将是一种廉价的，口服的小分子，将促进内源性免疫原子的表达，可为HIV-1采集提供交叉反应性免疫保护。这种方法能够在体外验证这种方法可保护HIV-1感染的交叉反应CD8 T细胞反应的能力。屏幕还将产生能够激活HIV-1的小分子，而不能产生用于对抗内存T细胞潜在的HIV-1感染的HERV LTR，以及能够抑制激活的HERV LTR的小分子，如果HERV激活有任何负面影响，则应提供解毒剂。这项新的研究建议将利用人类基因组中的病毒样元素与艾滋病毒/艾滋病病毒之间的相关性，以刺激免疫力，从而阻止或减缓HIV/AIDS病毒的传播。该方法将是唤醒正常静音的人内源性逆转录病毒元件，并从一个非常大的化合物库中选择的小分子，然后为人类免疫系统提供刺激。结果将是“交叉保护”的免疫力，这是通过与相关牛波克病毒疫苗接种消除天花的最佳体现。