Project 1: Analysis of 2nd phase decay in persons living with HIV

项目 1：艾滋病毒感染者第二阶段衰退分析

• 批准号: 10459661
• 负责人: ROBERT F SILICIANO
• 金额: $ 40.12万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10459661
• 关键词: Affect; Antigen Presentation; Apoptosis; Biological Assay; Blood; CD4 Positive T Lymphocytes; Cells; Characteristics; DNA; Data; Development; Evaluation; Frequencies; Gene Expression; Generations; HIV; HIV-1; Half-Life; Infection; Kinetics; Laboratories; Macaca; Measurement; Measures; Modeling; Mutation; Participant; Pathogenesis; Persons; Phase; Plasma; Population; Process; Production; Property; Proviruses; RNA; RNA I; Research Personnel; Research Project Grants; Resistance; SIV; Sampling; Sorting - Cell Movement; Testing; Transcription Coactivator; Transcription Repressor; Viral; Viral Genes; Viremia; Virus; antiretroviral therapy; design; digital; effective therapy; falls; genome sequencing; insight; integration site; novel; novel strategies; trafficking; transcriptomics; treatment duration

Summary – Project 1 The development of an accurate assay for plasma HIV-1 RNA provided important insights into HIV-1 pathogenesis and accelerated the development of effective treatments. Co-investigator Alan Perelson used frequent plasma HIV-1 RNA measurements to demonstrate a biphasic decay in viremia following the initiation of combination antiretroviral therapy (ART). Following a very rapid initial decay in the first days few days of treatment, viremia falls more slowly over the new few weeks. The half-lives of these two phases of decay of viremia (termed here 1st and 2nd phase) are 1 day and 14 days, respectively. Fundamental principles of viral dynamics2-4 developed by Dr. Perelson suggest that the biphasic decay must reflect the presence of two distinct populations of virus producing cells with corresponding decay rates 1 day and 14 days. However, this prediction has yet to be verified. Concomitant measurement of changes in infected cell frequencies following ART initiation has been complicated by several factors including the presence of large numbers of defective proviruses. The recent development of digital droplet PCR assays for intact proviruses has allowed us to make such measurements in persons living with HIV-1 (PLWH) who are initiating ART and in SIV-infected macaques. In this proposal, we focus on the 2nd phase of decay of viremia which continues for several weeks after the very rapid 1st phase decay has eliminated most productively infected cells. Our fundamental hypothesis is that the 2nd phase decay represents a selection process which determines which cells will enter the stable latent reservoir. Only cells that survive this phase of decay may be able to downregulate HIV-1 gene expression and enter the stable latent reservoir, which we have shown has half-life measured in years (3.7 years). Therefore, we will analyze 2nd phase decay to develop novel insights into the composition and dynamics of the latent reservoir that may suggest new strategies for curing HIV-1 infection.

摘要-项目1 血浆HIV-1RNA准确检测的发展为了解HIV-1提供了重要的见解 发病机制及加速发展的有效治疗方法。联合调查员艾伦·佩雷尔森用 频繁的血浆HIV-1RNA检测显示病毒血症开始后出现双相衰变 联合抗逆转录病毒疗法(ART)。在经历了最初几天非常迅速的腐烂之后 治疗后，病毒血症在新的几周里下降得更慢。这两个衰变阶段的半衰期 病毒血症(这里称为1期和2期)分别为1天和14天。病毒的基本原理 Perelson博士发展的动力学2-4表明，两相衰变必须反映出两种截然不同的 病毒产生细胞的数量，相应的衰减率分别为1天和14天。然而，这一预测 尚未得到证实。抗逆转录病毒治疗开始后感染细胞频率变化的伴随测量 有几个因素使情况变得复杂，包括存在大量有缺陷的前置文件。这个 最近对完整前病毒的数字液滴聚合酶链式反应分析的发展使我们能够做出这样的 对开始抗逆转录病毒治疗的HIV-1携带者(PLWH)和感染SIV的猕猴进行测量。在……里面 这项建议，我们把重点放在病毒血症的第二个衰变阶段，这个阶段在非常 快速的第一阶段腐烂已经消除了最具生产力的感染细胞。我们的基本假设是 第二相衰变是一种选择过程，它决定了哪些细胞将进入稳定潜伏期 水库。只有在这一腐烂阶段存活下来的细胞才能下调HIV-1基因的表达，并 进入稳定的潜在储集层，我们已经证明了它的半衰期是以年(3.7年)为单位的。因此， 我们将分析第二相衰变，以发展对潜伏期的组成和动力学的新见解。 这可能会为治愈HIV-1感染提出新的策略。