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: 10459934
• 负责人: Nadia R Roan
• 金额: $ 50.01万
• 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/10459934
• 关键词: Acute; Affect; Agonist; Back; 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; Lead; 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; base; 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.

项目摘要/摘要（项目 3） 联合抗逆转录病毒疗法 (ART) 可抑制 HIV 复制并降低死亡率 在艾滋病毒感染者中。然而，ART 并不能消除 HIV 感染细胞的储存库，并且 治疗中断或停止后，病毒通常会在几周内从该储存库反弹。虽然 长期以来，病毒库一直被认为是治愈艾滋病毒的主要障碍，其基本机制 病毒反弹以及具有反弹能力的储存细胞的性质仍然知之甚少。在这个项目中， 我们假设病毒转录活性和储存细胞的免疫状态都是关键决定因素 ART 停止时病毒反弹所需的时间，这些特征将定义早期目标 反弹时感染。为了检验这个假设，我们将实现各种高维单 细胞分析技术来定义 HIV 转录状态和 HIV 储存细胞的表型特征 作为正在进行的试验的一部分，艾滋病毒感染者 (PLWH) 正在接受分析治疗中断 (ATI)。这些 包括诊断后早期开始治疗的个体（急性感染的 Fiebigs I-V）和那些 在感染慢性期开始治疗。在目标 1 中，基于 ddPCR 和病毒测序 方法将用于表征储存细胞的完整性和 HIV 转录活性，同时 新的单细胞方法将用于询问转录活性和诱导型的表型 储存细胞。然后，该信息将与病毒从这些区域反弹所需的时间相关联。 个人。在治疗中断过程中将对这些相同的个体进行广泛采样，以便 更好地了解反弹时发生的早期事件，这些事件将在 目标 2。最后，目标 3 将使用类似的技术来描述另外两组接受过 ATI，但在以治疗为基础的干预措施的背景下，旨在通过免疫实现功能性治愈 调制。总的来说，这项研究将深入了解反弹病毒和宿主细胞的特征 主管储存细胞，并将这些知识与 ART 期间病毒反弹所需的时间联系起来 在正在进行的非介入性和介入性治愈临床试验的背景下进行中断。