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） 为了开发旨在治愈艾滋病毒或减少艺术治疗感染的后遗症的新疗法，有 对可能有助于免疫激活的HIV感染细胞持续性进行更多研究的批判性需要 关于艺术，并在艺术中断后允许病毒学反弹。反弹胜任的水库经常是 假定与潜在和/或完整储层相同，反弹病毒的序列通常会做 不匹配潜在储层的储层，而有时与与细胞相关的HIV RNA匹配的ART之前 中断。这些发现表明需要更好地了解在体内表达艾滋病毒的水库， 被毒死以引发艺术中断反弹，并可能有助于免疫激活，器官 损害和降低艺术的预期寿命。但是，先前对“转录活性储层”的研究 无法完全表征这些细胞的异质性，这些细胞因艾滋病毒的类型而变化 转录RNA（过程或完整，有缺陷或完整的Proviruse），以及它是否被翻译成 HIV蛋白。我们假设表达不同类型的HIV RNA和/或蛋白质的细胞子集将有所不同 就其频率，生存/清除率，对免疫激活的贡献，细胞基因表达， 和组织分布。为了调查这些假设，该项目将应用一系列新的和尖端 从不同临床表型中对纵向样品进行测定以：1）衡量不同的前期病毒 （完整/有缺陷），艾滋病毒转录，有缺陷或完整的艾滋病毒转录本和艾滋病毒GAG蛋白改变的块 随着时间的流逝，血液前后的艺术品以及它们在启动的精英控制者和个人之间的差异 急性或慢性感染期间的艺术； 2）确定每种类型的HIV RNA和蛋白质的水平如何相关 带有HIV特异性T和其他免疫复杂以及免疫激活/炎症的标志物； 3） 确定宿主细胞基因的差异表达（例如抗病毒因子）与这些能力的能力如何 细胞表达HIV并在血液和淋巴结中生存。随后的项目将调查如何不同 病毒和表达HIV的细胞的类型在其频率，表型和病毒/细胞基因上有所不同 在体内的整个组织中表达（项目＃2），以及它们在其上的不同 对旨在靶向和杀死艾滋病毒细胞的新型疗法的反弹和敏感性的贡献 （项目＃3）。