Dynamics, immune responses, and transcriptomics of the HIV-expressing reservoir on ART

ART 上 HIV 表达库的动态、免疫反应和转录组学

• 批准号: 10459932
• 负责人: Steven A Yukl
• 金额: $ 39.96万
• 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/10459932
• 关键词: Acute; Biological Assay; Blood; Cell Survival; Cells; Clonality; DNA; Development; Drug or chemical Tissue Distribution; Freedom; Frequencies; Gene Expression; Genes; Genetic Transcription; Goals; HIV; HIV Antibodies; HIV therapy; Heterogeneity; Immune; Immune response; Immunologic Markers; Individual; Infection; Inflammation; Interruption; Knowledge; Life Expectancy; Measures; Metabolic Clearance Rate; Nature; Organ; Phenotype; Population; Predisposition; Proteins; Proviruses; RNA; Research; Sampling; Series; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Time; Tissues; Transcript; Translating; Viral; acute infection; base; chronic infection; clinical phenotype; differential expression; effective therapy; gag Gene Products; immune activation; in vivo; lymph nodes; novel; novel therapeutics; single-cell RNA sequencing; therapy design; transcriptomics; viral RNA; viral rebound

Project Summary/Abstract (Project #1) To develop new therapies aimed at HIV cure or reducing the sequelae of ART-treated infection, there is a critical need for more research on the persistence of HIV-infected cells that can contribute to immune activation on ART and allow virologic rebound after ART interruption. While the rebound competent reservoir is often assumed to be the same as the latent and/or the intact reservoir, sequences from the rebound virus usually do not match those from the latent reservoir but sometimes match those from cell-associated HIV RNA prior to ART interruption. These findings suggest the need to better understand the reservoirs that express HIV in vivo, which are poised to initiate rebound on interruption of ART and likely contribute to the immune activation, organ damage, and reduced life expectancy on ART. However, prior studies of the “transcriptionally active reservoir” have not been able to fully characterize the heterogeneity of these cells, which vary in terms of the types of HIV RNA transcribed (processive or complete, from defective or intact proviruses) and whether it is translated into HIV protein. We hypothesize that subsets of cells expressing different types of HIV RNA and/or protein will differ in terms of their frequency, survival/clearance rate, contribution to immune activation, cellular gene expression, and tissue distribution. To investigate these hypotheses, this project will apply a series of new and cutting-edge assays to longitudinal samples fromdifferent clinical phenotypes in order to: 1) measure how different proviruses (intact/defective), blocks to HIV transcription, defective or intact HIV transcripts, and HIV Gag protein change over time pre- and post-ART in the blood and how they differ between elite controllers and individuals who initiate ART during acute or chronic infection; 2) determine how levels of each type of HIV RNA and protein correlate with HIV-specific T and other immune responses as well as markers of immune activation/inflammation; and 3) determine how differential expression of host cell genes (such as antiviral factors) relates to the ability of these cells to express HIV and survive in blood and lymph nodes. Subsequent projects will investigate how different types of proviruses and HIV-expressing cells differ in their frequencies, phenotypes, and viral/cellular gene expression throughout the full spectrum of tissues in the body (Project #2), and how they differ in their contribution to rebound and susceptibility to novel therapies designed to target and kill HIV-expressing cells (Project #3).

项目摘要/摘要（项目#1） 为了开发旨在治愈HIV或减少ART治疗感染后遗症的新疗法， 迫切需要对艾滋病毒感染细胞的持久性进行更多的研究，这些细胞可能有助于免疫激活 并允许ART中断后病毒学反弹。而回弹型储层往往 假定与潜伏和/或完整的储库相同，来自反弹病毒的序列通常 与潜伏库中的不匹配，但有时与ART前细胞相关HIV RNA的匹配 中断.这些发现表明，需要更好地了解体内表达HIV的宿主， 准备在ART中断时启动反弹，并可能有助于免疫激活，器官 然而，先前对“转录活性储库”的研究表明， 这些细胞因艾滋病毒的类型而异，目前还不能完全确定它们的异质性 RNA转录（进行性或完整，从缺陷或完整的前病毒），以及它是否被翻译成 HIV蛋白。我们假设表达不同类型HIV RNA和/或蛋白质的细胞亚群会有所不同， 就其频率、存活/清除率、对免疫激活的贡献、细胞基因表达 和组织分布。为了研究这些假设，该项目将应用一系列新的和前沿的 对来自不同临床表型的纵向样品进行测定，以便：1）测量不同的前病毒如何 （完整/缺陷）、HIV转录阻断、缺陷或完整HIV转录物和HIV Gag蛋白变化 随着时间的推移，在血液中的前和后ART以及精英控制者和启动ART的个人之间的差异 急性或慢性感染期间的ART; 2）确定每种类型的HIV RNA和蛋白质的水平如何相互关联 具有HIV特异性T和其他免疫应答以及免疫活化/炎症的标志物;以及3） 确定宿主细胞基因（如抗病毒因子）的差异表达如何与这些基因的能力相关。 细胞表达艾滋病毒，并在血液和淋巴结中存活。随后的项目将研究如何不同 前病毒和HIV表达细胞的类型在频率、表型和病毒/细胞基因方面不同， 表达在整个光谱的组织在体内（项目#2），以及他们如何不同，在他们的 有助于反弹和对旨在靶向和杀死HIV表达细胞的新疗法的敏感性 （项目#3）。