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: 7914339
• 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/7914339
• 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 cell response; T memory cell; Transcript; Vaccination; Viral load measurement; Virus; base; combat; cross reactivity; genetic linkage; novel; prevent; promoter; 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（由申请方提供）：在本提案中，我们计划通过激活人内源性逆转录病毒（HERV）元件的表达来引发对HIV-1的保护性免疫，HERV元件编码具有足够序列同源性的蛋白质，以产生交叉反应性免疫。使用正常沉默的内源性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连锁。大多数HERV基因座的转录已被长末端重复序列（LTR）区域的表观遗传变化沉默，本项目的目标是逆转这种表观遗传沉默，并促进两种HERV转录本（全长HERV-K102和pol相关HERV HCP 5）在淋巴细胞中的表达。这些HERV编码的蛋白质的表达将刺激免疫应答，该免疫应答将被证明与HIV-1抗原交叉反应。最初，我们将使用已知激活潜伏的HIV-1 LTR的药物，看看它们是否会激活选定的HERV LTR。然后，我们将表征表观遗传变化和启动子结合，区分潜伏的活化HERV LTR。利用这些知识，我们将转移到一个30万化合物库的小分子筛选，以鉴定能够激活HERV LTR而不是HIV-1 LTR的药物。最终产物将是一种廉价的、可口服的小分子，其将促进内源性免疫原的表达，所述内源性免疫原将提供针对HIV-1获得的交叉反应性免疫保护。将在体外验证该方法引发交叉反应性CD 8 T细胞应答的能力，该交叉反应性CD 8 T细胞应答对HIV-1感染具有保护作用。筛选还将产生能够激活HIV-1但不激活HERV LTR的小分子，用于对抗记忆T细胞的潜伏HIV-1感染，以及能够抑制激活的HERV LTR的小分子，如果HERV激活具有任何负面影响，则提供解毒剂。这项新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。该方法将是唤醒正常沉默的人类内源性逆转录病毒元件与小分子选择从一个非常大的库的化合物，这将提供一个刺激人类免疫系统。其结果将是“交叉保护”免疫，最好的例子是通过接种相关的牛痘病毒根除天花。