Cross-reactive HERV immunity to combat HIV-1 infection

描述（由申请人提供）：在本提案中，我们计划通过激活人类内源性逆转录病毒（HERV）元件的表达来引发对HIV-1的保护性免疫，这些元件编码具有足够的序列同源性以产生交叉反应性免疫的蛋白质。使用通常沉默的内源性基因作为内部免疫原是基于最近的数据显示HERV和HIV-1肽之间的交叉反应性以及人类基因组中HERV位点与HIV-1病毒载量控制之间的令人兴奋的遗传联系。大多数HERV基因位点的转录被长末端重复（LTR）区域的表观遗传改变所沉默，本项目的目标是逆转这种表观遗传沉默，并促进两种HERV转录物（全长HERV- k102和pol相关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，并将被证明与HIV-1抗原发生交叉反应。最初，我们将使用已知的激活潜伏HIV-1 ltr的药物，看看它们是否会激活选定的HERV ltr。然后，我们将描述区分潜伏和活化HERV lts的表观遗传变化和启动子结合。利用这些知识，我们将转向30万个化合物文库的小分子筛选，以确定能够激活HERV ltr而不是HIV-1 ltr的药物。最终产品将是一种廉价的、可口服的小分子，它将促进内源性免疫原的表达，从而提供抗HIV-1获得的交叉反应性免疫保护。这种方法引发CD8 T细胞交叉反应的能力，对HIV-1感染具有保护作用，将在体外验证。筛选还将产生能够激活HIV-1但不能激活HERV LTRs的小分子，用于对抗潜伏的HIV-1记忆T细胞感染，以及能够抑制激活的HERV LTRs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病毒样元素与艾滋病毒/艾滋病病毒之间的相关性来刺激免疫，从而防止或减缓艾滋病毒/艾滋病病毒的传播。该方法将是用从一个非常大的化合物文库中选择的小分子唤醒正常沉默的人类内源性逆转录病毒元素，然后为人类免疫系统提供刺激。其结果将是“交叉保护”免疫，通过接种相关牛痘病毒根除天花就是最好的例证。

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.