HIV-1 Gene Suppression by CD8+ T Cells

CD8 T 细胞抑制 HIV-1 基因

• 批准号: 7495482
• 负责人: GEORGIA Doris TOMARAS
• 金额: $ 35.81万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7495482
• 关键词: Affect; Anti-Retroviral Agents; Antiviral Agents; Antiviral Response; Biological Assay; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Chimera organism; Chromatin Structure; Coculture Techniques; Data; Disease; Epigenetic Process; Evaluation; Event; Gene Expression; Genes; Genetic Transcription; Genome; Goals; HIV; HIV Infections; HIV vaccine; HIV-1; Histone Deacetylase; Human; Immune response; In Vitro; Infection prevention; Laboratories; Length; Link; Maps; Mediating; Molecular; Molecular Cloning; Mutation; Nuclear Extract; Outcome; Outcome Study; Pathway interactions; Patients; Phenotype; Play; Proviruses; Public Health; RNA Splicing; Regulation; Repression; Resistance; Resources; Role; SP1 gene; Site-Directed Mutagenesis; T-Lymphocyte; Testing; Therapeutic Intervention; Time; Today; Transactivation; Transcription Initiation; Transcriptional Regulation; Treatment Protocols; Up-Regulation; Vaccination; Vaccine Design; Vaccines; Viral; Viremia; Virus; Virus Latency; Virus Replication; Work; autologous lymphocytes; base; c-myc Genes; chromatin remodeling; cis acting element; concept; design; gene repression; genetic element; in vivo; novel; protein expression; tat Protein; vaccination strategy; virus genetics

DESCRIPTION (provided by applicant): Elimination of HIV replication in vivo has not been achieved to date because HIV establishes and persists in a latent state in host cells. Although attempts have been made to activate and eliminate these reservoirs, the most potent antiretroviral regimens in use today do not eradicate HIV from its latent state. For HIV, it is not known how provirus latency is induced and maintained in vivo. A better understanding of whether host immune responses are involved in HIV latency is needed. We have determined that noncytolytic CD8 suppression occurs during the time of virus gene expression and inhibits the initiation of virus transcription. We now have evidence that the same epigenetic changes that occur during provirus latency also occur as a result of noncytolytic CD8 suppression. We propose to build upon this novel finding to determine if noncytolytic CD8 suppression is directly involved in HIV latency. The molecular events of chromatin remodeling required for transcriptional regulation will be examined to determine the linkage between noncytolytic CD8 suppression and provirus latency. Analyses of chimeras of genetically related pair of viruses with opposing sensitivities to CD8 suppression will determine if the resistant virus phenotype results from molecular changes required for latency. The results from this study can provide a better understanding of the current limitations of antiretrovirals, in addition to immediately altering candidate HIV vaccine design and evaluation. Potential implications of this work are that noncytolytic CD8 T cells would be of benefit for disease-modifying vaccine strategies aimed to reduce peak viremia and set point, but would not be of benefit for preventative vaccine strategies. This study has two specific aims: 1. Determine if noncytolytic CD8+ T cell mediated HIV suppression causes HIV latency. 2. Identify the viral genetic changes linked to noncytolytic CD8 resistance and determine the role of latency. PUBLIC HEALTH RELEVANCE: Noncytolytic CD8 T cell mediated suppression plays an important role in viral control in natural HIV infection and thus could be an important immune response to elicit by vaccination. Conversely, the elicitation of this immune response may be undesirable if a protective vaccination strategy is the goal. The results from this study will determine if induction of noncytolytic CD8 T cells would be beneficial in a protective vaccination strategy or whether it should be restricted to disease-modifying vaccine strategies.

描述（由申请方提供）：迄今为止尚未实现消除体内HIV复制，因为HIV在宿主细胞中以潜伏状态建立并持续存在。尽管已经尝试激活和消除这些储存库，但目前使用的最有效的抗逆转录病毒疗法并不能将艾滋病毒从潜伏状态中根除。对于HIV，尚不清楚原病毒潜伏期如何在体内诱导和维持。需要更好地了解宿主免疫反应是否参与HIV潜伏期。我们已经确定，非细胞溶解性CD8抑制发生在病毒基因表达的时间，并抑制病毒转录的启动。我们现在有证据表明，在前病毒潜伏期发生的表观遗传变化也是由于非细胞溶解性CD8抑制而发生的。我们建议建立在这一新的发现，以确定非细胞溶解性CD8抑制是否直接参与HIV潜伏期。将检查转录调节所需的染色质重塑的分子事件，以确定非细胞溶解性CD8抑制和前病毒潜伏期之间的联系。分析对CD8抑制具有相反敏感性的遗传相关病毒对的嵌合体，将确定耐药病毒表型是否由潜伏期所需的分子变化引起。这项研究的结果可以更好地了解目前抗逆转录病毒药物的局限性，以及立即改变候选HIV疫苗的设计和评估。这项工作的潜在意义是，非细胞溶解性CD8 T细胞将有利于疾病修饰疫苗策略，旨在减少峰值病毒血症和设定点，但不会有利于预防性疫苗策略。本研究有两个具体目的：1。确定非细胞溶解性CD8+ T细胞介导的HIV抑制是否导致HIV潜伏期。2.确定与非细胞溶解性CD8抗性相关的病毒遗传变化，并确定潜伏期的作用。 公共卫生关系：非细胞溶解性CD8 T细胞介导的抑制在自然HIV感染的病毒控制中起重要作用，因此可能是通过疫苗接种引发的重要免疫应答。相反，如果保护性疫苗接种策略是目标，则这种免疫应答的引发可能是不期望的。这项研究的结果将确定非细胞溶解性CD8 T细胞的诱导是否有利于保护性疫苗接种策略，或者是否应将其限制在疾病修饰疫苗策略中。