A New Approach to Reactivating HIV from Latency

重新激活潜伏期艾滋病毒的新方法

• 批准号: 9977118
• 负责人: ASHLEY T. HAASE
• 金额: $ 60.04万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977118
• 关键词: Active Sites; Anatomy; Attenuated; Biological Assay; CD4 Positive T Lymphocytes; Cell Culture Techniques; Cells; Cellular Assay; Coupled; Data; Development; Epigenetic Process; Evaluation; Failure; Feedback; Gene Expression; Gene Silencing; Genetic Transcription; Genome; Goals; Growth; HIV; HIV Genome; HIV Infections; Histone Deacetylase Inhibitor; In Vitro; Infection; Interphase Cell; Interruption; Intervention; Investigation; Lead; Lentivirus Vector; Lymphoid Tissue; Measurement; Measures; Medical History; Methods; Mitogens; Patients; Proviruses; RNA Viruses; Sampling; Shock; Supplementation; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Transactivation; Viral; Virus; antiretroviral therapy; base; cofactor; genome analysis; immune clearance; improved; in vitro Assay; in vivo; latent infection; novel strategies; peripheral blood; reactivation from latency; small molecule; tat Genes; vector-induced

SUMMARY/ABSTRACT Combination antiretroviral therapy (ART) can control but not cure HIV infection because of reservoirs, particularly latently infected CD4 T cells, established before ART was begun, from which infection rebounds if ART is interrupted. To achieve a functional cure or eradication of this reservoir, “shock and kill” strategies seek to reactivate latently infected CD4+ T-cells for elimination by immune or other mechanisms, but current methods for reactivation predicated on the concept that harbor HIV proviruses that have been transcriptionally silenced by epigenetic or other mechanisms have proven quite inefficient in reversing latency. This proposal describes a new approach to reactivating latently infected cells by lentivirus vector induced expression of the HIV tat gene. Preliminary results provide evidence of extraordinary efficiency of Tat-reactivation and the underpinnings for an in vitro latency reactivation assay with new single cell measurements of the latently infected cell reservoir from which infection will rebound if ART is interrupted. The Specific Aims of the proposal are to 1) further develop the Tat-reactivation assay as a faster and more accurate assay for reservoir evaluations in peripheral blood (PB) and lymphoid tissues (LT); determine the correlations between single cell measurements of virus producing cells, cells with intact HIV genomes and current quantitative virus growth assays; and 2) apply the assay to assess the impact of ART in very early stage infection to limit the size of HIV reservoirs in PB and LT. peripheral blood (PB) and lymphoid tissues (LT). The long-term goal of investigation of Tat-reactivation is development of more effective approaches to the “shock” component of shock and kill approaches to reducing HIV reservoirs.

摘要/摘要 联合抗逆转录病毒疗法(ART)可以控制但不能治愈艾滋病毒感染， 尤其是在抗逆转录病毒治疗开始前建立的潜伏感染的CD4T细胞，如果 艺术被打断了。为了实现治愈或根除这种蓄水池的功能，“电击并杀死”战略寻求 重新激活潜伏感染的CD4+T细胞以通过免疫或其他机制消除，但目前 基于携带已转录的HIV前病毒的概念的重新激活方法 被表观遗传或其他机制沉默已被证明在逆转潜伏期方面相当低效。这项建议 描述了一种通过慢病毒载体诱导表达潜伏感染的细胞来重新激活细胞的新方法 HIV TAT基因。初步结果提供了TAT重新激活的非凡效率和 用新的潜伏期单细胞测量为体外潜伏期再激活试验奠定基础 如果ART被中断，感染将从其中反弹的受感染细胞储存库。该提案的具体目的 1)进一步发展TAT复活法，使之成为一种更快速、更准确的水库检测方法。 外周血(PB)和淋巴组织(LT)的评估；确定单细胞之间的相关性 病毒产生细胞、具有完整HIV基因组的细胞和当前定量病毒生长的测量 检测；以及2)应用检测来评估抗逆转录病毒疗法在早期感染中的影响，以限制艾滋病毒的大小。 PB和LT的储集层。外周血(PB)和淋巴组织(LT)。调查的长期目标 重新激活TAT的关键是开发出更有效的方法来处理休克和杀戮的“休克”成分 减少艾滋病毒宿主的方法。