Reservoir features associated with time-to-rebound during analytical treatment interruption

与分析处理中断期间的反弹时间相关的储层特征

• 批准号: 10614027
• 负责人: Nadia R Roan
• 金额: $ 39.51万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614027
• 关键词: Acute; Affect; Agonist; Back; Binding; Bioinformatics; Biological Assay; Cells; Chronic; Chronic Phase; Clinical Trials; Combined Modality Therapy; Diagnosis; Drug or chemical Tissue Distribution; Early treatment; Event; Foundations; Funding; Genetic Transcription; Genome; HIV; HIV therapy; Immune; Individual; Infection; Interruption; Intervention; Knowledge; Leukapheresis; Measurement; Methods; Monitor; Nature; Participant; Patients; Persons; Phenotype; Plasma; Property; Proviruses; RNA; Recrudescences; Sampling; Source; Specimen; Techniques; Technology; Testing; Time; Transcript; Vaccine Therapy; Viral; Viral reservoir; Viremia; Virus; acute infection; antiretroviral therapy; chimeric antigen receptor T cells; chronic infection; cohort; genome sequencing; high dimensionality; immunoregulation; intervention effect; mortality; novel; single cell analysis; single-cell RNA sequencing; tool; viral rebound

Project Summary/Abstract (Project 3) Combination antiretroviral therapy (ART) can suppress HIV replication and lead to decreased mortality in HIV-infected individuals. However, ART does not eliminate the reservoir of HIV-infected cells, and upon treatment interruption or cessation, virus typically rebounds from this reservoir within several weeks. Although the viral reservoir has long been recognized as the main barrier to curing HIV, the basic mechanisms underlying viral rebound, and the nature of the rebound-competent reservoir cells, remain poorly understood. In this Project, we hypothesize that both viral transcriptionally activity and immune states of reservoir cells are key determinants of the time it takes for virus to rebound when ART is stopped, and that these features will define the early targets of infection at the time of rebound. To test this hypothesis, we will implement a variety of high-dimensional single- cell analysis techniques to define the HIV transcriptional state and phenotypic features of HIV reservoir cells in people living with HIV (PLWH) undergoing analytical treatment interruption (ATI) as part of ongoing trials. These include individuals who initiated treatment early after diagnosis (Fiebigs I-V of acute infection) and those who initiated treatment during the chronic phase of infection. In Aim 1, ddPCR- and viral sequencing-based approaches will be used to characterize the intactness and HIV transcriptional activity of reservoir cells, while novel single-cell methods will be used to interrogate the phenotypes of transcriptionally-active and inducible reservoir cells. This information will then be associated with the time it takes virus to rebound from these individuals. These same individuals will be extensively sampled over the course of treatment interruption in order to better understand the early events occurring at the time of rebound, which will be extensively characterized in Aim 2. Finally, Aim 3 will use similar techniques to characterize two additional cohorts of individuals undergoing ATI, but in the context of cure-based interventions aimed at achieving a functional cure through immune modulation. Overall, this study will establish an in-depth view of the viral and host cell features of rebound- competent reservoir cells, and will relate this knowledge to the time it takes for viral rebound during ART interruption, in the context of ongoing non-interventional and interventional cure-based clinical trials.

项目概要/摘要（项目3） 联合抗逆转录病毒疗法（ART）可以抑制HIV复制，降低死亡率 在HIV感染者身上。然而，ART并不能消除HIV感染细胞的储存库， 治疗中断或停止后，病毒通常在几周内从该储库反弹。虽然 长期以来，病毒储存库一直被认为是治疗HIV的主要障碍，其基本机制是 病毒反弹和具有反弹能力的储库细胞的性质仍然知之甚少。在本项目中， 我们假设病毒的转录活性和储库细胞的免疫状态都是关键的决定因素， 当ART停止时病毒反弹所需的时间，这些特征将确定早期目标 在反弹的时候感染。为了验证这一假设，我们将实现各种高维单- 细胞分析技术，以确定艾滋病毒的转录状态和表型特征的艾滋病毒水库细胞， 作为正在进行的试验的一部分，正在接受分析性治疗中断（ATI）的艾滋病毒感染者（PLWH）。这些 包括在诊断后早期开始治疗的个体（急性感染的Fiebigs I-V）和 在感染的慢性阶段开始治疗。在目标1中，基于ddPCR和病毒测序的 方法将用于表征储库细胞的完整性和HIV转录活性， 新的单细胞方法将用于询问转录活性和诱导型的表型。 储库细胞然后，这些信息将与病毒从这些位置反弹所需的时间相关联。 个体在治疗中断期间，将对这些相同的个体进行广泛采样， 为了更好地了解在反弹时发生的早期事件，这将广泛地表现在 目标2.最后，Aim 3将使用类似的技术来描述另外两个接受治疗的个体队列， ATI，但在治疗为基础的干预，旨在实现功能性治愈，通过免疫治疗的背景下， 调变总的来说，这项研究将建立一个深入的看法，病毒和宿主细胞的特点反弹- 并将这些知识与ART期间病毒反弹所需的时间联系起来 在正在进行的非干预性和干预性治疗临床试验的背景下中断。