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: 10599360
• 负责人: ROBERT F SILICIANO
• 金额: $ 51.44万
• 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/10599360
• 关键词: Acceleration; Affect; Antigen Presentation; Apoptosis; Biological Assay; Blood; CD4 Positive T Lymphocytes; Cell Survival; 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; Productivity; Property; Proviruses; RNA; RNA I; Research Personnel; Research Project Grants; Resistance; SIV; Sampling; Sorting; 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-1 RNA的精确测定的发展为HIV-1的研究提供了重要的见解 发病机制，并加速了有效治疗方法的发展。共同研究员艾伦·佩雷尔森使用 频繁的血浆HIV-1 RNA测量，以证明病毒血症开始后的双相衰减。 联合抗逆转录病毒治疗（ART）。在最初的几天里， 在新的几周内，病毒血症福尔斯下降得更慢。这两个衰变阶段的半衰期 病毒血症（在此称为第一和第二阶段）分别为1天和14天。病毒的基本原理 Perelson博士开发的动力学2 -4表明，双相衰变必须反映两种不同的 病毒产生细胞群，具有1天和14天的相应衰减率。然而，这一预测 还有待核实。ART启动后感染细胞频率变化的伴随测量 由于包括存在大量有缺陷的前病毒在内的几个因素而变得复杂。的 针对完整前病毒的数字液滴PCR测定的最新发展使我们能够进行这样的 在HIV-1感染者（PLWH）中开始ART和SIV感染的猕猴中进行测量。在 在这个建议中，我们关注的是病毒血症衰变的第二阶段，这一阶段在病毒血症发生后持续了几周。 快速的第一阶段衰变已经消除了大多数生产性感染的细胞。我们的基本假设是 第二阶段衰减代表了一个选择过程，它决定了哪些细胞将进入稳定的潜伏期。 水库只有在这个衰变阶段存活下来的细胞才能下调HIV-1基因的表达， 进入稳定的潜在储存库，我们已经表明其半衰期以年为单位（3.7年）。因此，我们认为， 我们将分析第二阶段的衰变，以发展新的见解的组成和动力学的潜在的 这可能为治疗HIV-1感染提出新的策略。