Elucidation of the Mechanisms of CD8+ T Cell Noncytolytic Antiviral Response

描述（由申请人提供）：感染细胞。这种类型的非细胞溶解性抑制被称为CD 8 + T细胞非细胞溶解性抗病毒反应（CNAR）。CNAR的机制尚未被表征，但其重要性通过CNAR与HIV感染个体的健康临床状态的相关性得到证明。我们的长期目标是弄清CNAR的机制，以便我们能够学习如何引起或模仿这种反应。目前的研究表明，一种未知的分子或分子复合物在病毒转录开始时阻断了HIV-1的复制。我们的目标是分析两个分支的转录调控宿主表观遗传学和病毒遗传元件，以确定CNAR的机制和关键分子负责。拟议的工作将集中在假设CNAR诱导转录抑制因子，如组蛋白脱乙酰酶抑制HIV-1前病毒的转录，HIV-1可以突变其基因组，以抵消这些转录抑制因子的影响。初步数据表明，抑制组蛋白去乙酰化导致CNAR降低;随着时间的推移，遗传相关的HIV-1分离株对CNAR的敏感性不同。我们将通过在敏感病毒和抗性病毒之间创造嵌合病毒来鉴定赋予抗性的遗传元件。此外，我们将使用染色质免疫沉淀检查组蛋白去乙酰化酶1的招聘和其对CNAR抑制培养物中CD 4 + T细胞的HIV-1长末端重复内核心组蛋白乙酰化的影响。我们的研究将提供一个更好的了解介导的分子，CNAR的机制，并在开发新的抗病毒药物，模拟或诱导这种免疫反应的援助。这项研究将确定CD 8 + T细胞如何抑制HIV-1而不杀死感染的细胞。确定这种免疫反应的机制将提供对HIV感染中宿主病原体相互作用的更好理解，并可能导致新的HIV治疗方法的开发。

DESCRIPTION (provided by applicant): the infected cell. This type of noncytolytic suppression is called CD8+ T cell noncytolytic antiviral response (CNAR). The mechanisms of CNAR are as yet uncharacterized, but its importance is evidenced by CNAR's correlation with healthy clinical status in HIV-infected individuals. It has been a long-term goal of ours to discern the mechanisms of CNAR, so that we can learn how to elicit or mimic this response. The current research suggests that an unknown molecule or complex of molecules block HIV-1 replication at the initiation of virus transcription. We aim to analyze two branches of transcription regulation-host epigenetics and viral genetic elements-to identify the mechanisms of CNAR and the key molecules responsible. The proposed work will be focused on the hypothesis that CNAR induces transcriptional repressors such as histone deacetylases to suppress transcription from HIV-1 provirus; and that HIV-1 can mutate its genome to negate the effects of these transcriptional repressers. Preliminary data has shown that inhibiting histone deacetylation results in a decrease in CNAR; and that genetically-related HIV-1 isolates evolve differing sensitivities to CNAR over time. We will identify genetic elements that confer resistance by creating chimeric viruses between sensitive and resistant viruses. Also, we will use chromatin immunoprecipitation to examine the recruitment of histone deacetylase 1 and its effects on acetylation of core histones within the HIV-1 long terminal repeat of CD4+ T cells in CNAR suppression cultures. Our study will provide a better understanding of the molecules that mediate CNAR, the mechanisms of CNAR, and aid in developing novel antivirals that mimic or induce this immune response. The proposed research will define how CD8+ T cells suppress HIV-1 without killing the infected cell. Determining the mechanism of this immune response will provide a greater understanding of the host pathogen-interaction in HIV infection and potentially lead to the development of novel HIV therapeutics.