Innate Sensing of Cell-Free DNA and the Interferon-Mediated Control of HIV In Vivo

无细胞 DNA 的先天感知和体内干扰素介导的 HIV 控制

• 批准号: 10620085
• 负责人: Satish Kumar Pillai
• 金额: $ 29.09万
• 依托单位: VITALANT
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620085
• 关键词: Acceleration; Advanced Development; Aftercare; Aging; Apoptosis; Binding; Biological Markers; CD4 Positive T Lymphocytes; Cell Death; Cells; Characteristics; Chronic; Circulation; Clinical; Clinical Oncology; Collection; Cytidine Deaminase; DNA Packaging; Data; Death Rate; Dimensions; Disease; Disease remission; Enabling Factors; Evaluation; Exhibits; HIV; HIV Antibodies; HIV Infections; Human body; Immune; Immunologics; Individual; Inflammation; Inflammatory; Integration Host Factors; Interferon Type I; Interferons; Interruption; Kinetics; Link; Macrophage; Measurement; Measures; Mediating; Mitochondrial DNA; Molecular; Morbidity - disease rate; Mutation; Nucleic Acids; Phenotype; Plasma; Plasma Cells; Predisposition; Recrudescences; Recurrent disease; Refractory; Sampling; Selection for Treatments; Signal Transduction; Study Section; System; Time; Viral; Virus Latency; antiretroviral therapy; antiviral immunity; cancer diagnosis; cell free DNA; cohort; cytokine; diagnostic strategy; disorder risk; experience; extracellular vesicles; in vivo; interest; liquid biopsy; methylome; mitochondrial dysfunction; monocyte; mortality; next generation sequencing; pharmacologic; prevent; prognostic significance; response; transmission process; uptake; viral rebound

PROJECT SUMMARY While the advent of antiretroviral therapy (ART) has dramatically reduced the morbidity and mortality associated with HIV infection, a cure is not achieved due to the persistence of latently-infected cells during treatment. Accumulating data suggest that HIV-infected individuals often experience persistent immune dysregulation, chronic inflammation, and accelerated aging even in the setting of ART-mediated viral suppression. These realities have created a pronounced interest in developing strategies to cure HIV infection. Identifying the host molecular determinants of HIV persistence and rebound kinetics following cessation of antiretroviral therapy (ART) will be critical in developing effective strategies to cure HIV infection. We recently applied a comprehensive systems profiling approach to plasma samples from HIV-infected individuals who underwent analytical treatment interruption (ATI), to identify circulating host factors that enable prediction of HIV rebound kinetics following ART interruption, and serve as potential pharmacological targets to promote durable virologic remission in the absence of ART. The host factor exhibiting the strongest statistical association with HIV rebound timing following ART cessation was circulating cell-free DNA (cfDNA) in plasma. Specifically, increased cfDNA abundance in plasma was associated with delayed time-to-rebound. cfDNA, released into circulation during programmed cell death, has been exploited extensively in the realm of clinical oncology (often termed “liquid biopsy”). However, cfDNA remains largely unexplored in the setting of HIV infection. In this R01 proposal, we rigorously explore cfDNA as a biomarker of HIV disease states, and we investigate the molecular and immunologic mechanisms linking cfDNA to viral expression and rebound. Our central hypotheses are that 1) cfDNA reflects the death rate of HIV-infected cells in vivo; and 2) cfDNA promotes an antiviral state in the host (e.g. induction of type I interferon response) which prevents viral rebound. Our project features an investigative team with basic, translational, and clinical expertise, and leverages large collections of clinical samples from well-characterized HIV-infected individuals. In Aim 1, we will apply next-generation sequencing (NGS) approaches to plasma samples from HIV-infected individuals to extend and enhance the prognostic significance of cfDNA as a biomarker of natural HIV control in vivo. In Aim 2, we will evaluate how the uptake and sensing of cfDNA by HIV target cells impacts cell fate and the reactivation and replication of HIV. In Aim 3, we will determine how HIV-associated mitochondrial dysfunction leads to cfDNA extrusion and ultimately induces type I interferon responses that prevent HIV rebound. Our project will advance the development and evaluation of HIV cure strategies.

项目摘要 而抗逆转录病毒疗法（ART）的冒险大大降低了发病率和死亡率 与HIV感染相关，由于在 治疗。累积数据表明，感染HIV的个体通常会经历持续的免疫 即使在ART介导的病毒的情况下，甚至在ART介导的病毒的情况下，功能障碍，慢性炎症和加速衰老 抑制。这些现实对制定治愈艾滋病毒感染的策略产生了明显的兴趣。 停止后，确定HIV持久性和反弹动力学的宿主分子决定剂 抗逆转录病毒疗法（ART）对于制定有效治愈HIV感染的策略至关重要。我们最近 将全面的系统分析方法应用于来自艾滋病毒感染者的血浆样本 经过分析治疗中断（ATI），以确定能够预测的循环宿主因素 ART中断后的HIV反弹动力学，并作为促进的潜在药物靶标 在没有艺术的情况下，耐用的病毒学缓解。显示强统计的宿主因素 与艾滋病毒抗ugh的hiv反弹时机相关联于循环无细胞的DNA（CFDNA） 等离子体。具体而言，血浆中的CFDNA抽象增加与延迟的时间延迟有关。 在编程细胞死亡期间发行的CFDNA已在 临床肿瘤学（通常称为“液体活检”）。但是，CFDNA在很大程度上仍然是出乎意料的 艾滋病毒感染。在此R01提案中，我们严格探索CFDNA作为HIV疾病状态的生物标志物，我们 研究将CFDNA与病毒表达和反弹联系起来的分子和免疫机制。 我们的中心假设是1）CFDNA反映了体内HIV感染细胞的死亡率；和2） CFDNA促进宿主中的抗病毒状态（例如，I型干扰素反应的诱导） 防止病毒反弹。我们的项目由一个基本，翻译和临床的调查团队 专业知识，并利用来自特征良好的HIV感染者的大量临床样本。 在AIM 1中，我们将对来自HIV感染的血浆样品应用下一代测序（NGS）方法 个人扩展和增强CFDNA作为自然艾滋病毒控制的生物标志物的预后意义 体内。在AIM 2中，我们将评估HIV靶细胞对CFDNA的摄取和敏感性如何影响细胞命运和 HIV的重新激活和复制。在AIM 3中，我们将确定如何与HIV相关的线粒体 功能障碍导致CFDNA扩展，并最终诱导I型干扰反应，以预防HIV 反弹。我们的项目将推进HIV治疗策略的开发和评估。