Investigating antigen-driven clonal proliferation to target HIV-1 persistence

研究抗原驱动的克隆增殖以靶向 HIV-1 持久性

• 批准号: 10693343
• 负责人: Francesco Roberto Simonetti
• 金额: $ 40.94万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-14 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10693343
• 关键词: Acceleration; Achievement; Anti-Retroviral Agents; Antifungal Agents; Antigens; Automobile Driving; Award; CD4 Positive T Lymphocytes; Candida; Candida albicans; Caring; Cell Survival; Cell division; Cells; Chronic; Clonal Expansion; Clone Cells; Collaborations; Communication; Cytomegalovirus; DNA; Decision Making; Dedications; Development; Disease Progression; Disease remission; Doctor of Philosophy; Educational process of instructing; Epidemic; Equipment; Event; Evolution; Exposure to; Faculty; Funding; Goals; HIV; HIV Antigens; HIV Genome; HIV Infections; HIV-1; Health system; Homeostasis; Human; Immune response; Immune system; Immunologic Factors; In Vitro; Individual; Infection; Institution; Interruption; Knowledge; Learning; Life; Maintenance; Measures; Medicine; Mentors; Mission; Morbidity - disease rate; National Cancer Institute; National Institute of Allergy and Infectious Disease; Outcome; Paper; Pathogenicity; Pennsylvania; Persons; Pharmaceutical Preparations; Physiological; Play; Population; Postdoctoral Fellow; Prevention; Principal Investigator; Process; Proliferating; Proteins; Public Health; Publishing; Research; Role; Running; Science; Scientist; Shapes; Source; Structure; Student recruitment; Students; T cell reconstitution; T-Cell Proliferation; T-Lymphocyte; Testing; Time; Training; United States National Institutes of Health; Universities; Viral; Virus; Work; Yeasts; adaptive immune response; adaptive immunity; antiretroviral therapy; career; career development; chronic infection; clinical training; commensal microbes; decay acceleration; design; effective intervention; experience; experimental study; graduate school; immune clearance; in vivo; innovation; insight; interest; lonely individuals; member; mortality; next generation; novel therapeutic intervention; pathogen; pressure; prevent; professor; programs; purge; senior faculty; skills; tool; undergraduate student; viral rebound

PROJECT SUMMARY Antiretroviral therapy (ART) greatly reduces HIV morbidity and mortality. However, it has no effect on the HIV reservoir, a small pool of latently infected cells that rekindles infection upon treatment interruption. Due to the persistence of this reservoir, ART must be continued indefinitely, requiring public health systems to deliver medications to all 38 million people living with HIV for life. This research program has the long-term goal of helping develop new therapeutic approaches to eliminate or control the HIV reservoir, leading to a drug-free remission. The proliferation of infected cells is a major mechanism of HIV persistence, as it results in expanded CD4+ T cell clones that carry proviral DNA. Recent studies suggest that antigen-specific immune responses contribute largely to this phenomenon. The overall objective of this application is to understand the role of chronic antigens in determining the structure and dynamics of the clones that constitute the HIV reservoir. The underlying central hypothesis is that adaptive immune responses impose selective pressure on HIV-infected cells. The rationale for the project is that, if clonal expansion is one of the major mechanisms of HIV persistence, targeting this process will reduce the reservoir size and accelerate its decay. The central hypothesis will be tested by pursuing three specific aims: 1) Determine the effect of antigens on HIV latency reversal; 2) Identify the factors responsible for the expansion and maintenance of HIV-infected, antigen-specific clones; and 3) Determine the role of chronic antigens from commensal pathogens in driving reservoir persistence. Under the first aim, CD4+ T cells reactive to Cytomegalovirus (CMV, the virus responsible for a common chronic infection) will be isolated from individuals with HIV and expanded ex vivo. Upon stimulation of T cells with cognate CMV antigens, HIV latency will be studied at the single-cell level and compared to non-specific maximal T cell stimulation, commonly used to reverse latency in vitro. For the second aim, CMV-responsive clones harboring HIV will be tracked longitudinally in individuals with CMV replication around the time of ART introduction, in the effort to understand the events underlying their expansion. For the third aim, Candida albicans, a pathogenic commensal yeast that plays a major role in driving antifungal immune responses, will be used to demonstrate whether chronic exposure to commensal microbes shapes the repertoire of CD4+ T cells, including those part of the HIV reservoir. The research proposed in this application is innovative because, compared to the status quo, it focuses on physiological T cell stimulation and ubiquitous immune responses to study latency reversal and HIV dynamics. The proposed research is significant because it is expected to result in a better understanding of the interaction between adaptive immunity and HIV persistence, and will provide new insight on how to target a major mechanism of HIV reservoir maintenance. Ultimately, such knowledge has the potential of offering new opportunities for the development of innovative strategies to induce HIV remission.

项目摘要 抗逆转录病毒疗法（ART）大大降低了HIV的发病率和死亡率。但是，它对艾滋病毒没有影响 储层是一小部分潜在感染的细胞，在治疗中断时重新引起感染。由于 该水库的持续存在，必须无限期地继续进行艺术，要求公共卫生系统交付 所有3800万艾滋病毒终生的药物。该研究计划的长期目标 帮助开发新的治疗方法来消除或控制艾滋病毒水库，从而无毒 缓解。感染细胞的增殖是HIV持久性的主要机制，因为它导致扩大 携带前病毒DNA的CD4+ T细胞克隆。最近的研究表明抗原特异性免疫反应 在很大程度上促进了这一现象。该应用的总体目的是了解慢性的作用 抗原确定构成HIV储层的克隆的结构和动力学。基础 中心假设是自适应免疫反应对感染HIV感染的细胞施加选择性压力。这 该项目的理由是，如果克隆扩张是艾滋病毒持久性的主要机制之一，则针对 此过程将减少储层尺寸并加速其衰减。中心假设将通过 追求三个具体目标：1）确定抗原对艾滋病毒潜伏期逆转的影响； 2）确定因素 负责扩大和维持HIV感染的抗原特异性克隆； 3）确定 来自共生病原体的慢性抗原在驱动储层持久性中的作用。在第一个目标下，CD4+ T细胞对巨细胞病毒的反应（CMV，导致常见慢性感染的病毒）将被分离 来自患有艾滋病毒和体内的人。用同源CMV抗原刺激T细胞后，HIV 等待时间将在单细胞水平上研究，并与非特异性最大T细胞刺激进行比较，通常 用于体外逆转潜伏期。为了第二个目标，将追踪携带HIV的CMV响应克隆 在艺术介绍时期，在CMV复制的个体中纵向努力，以了解 他们扩展的事件。对于第三个目标，白色念珠菌，一种致病性的共生酵母 在驱动抗真菌免疫反应中起着重要作用，将用于证明是否慢性暴露 对于共生微生物，塑造了CD4+ T细胞的曲目，包括HIV储层的一部分。这 在本应用程序中提出的研究具有创新性，因为与现状相比，它的重点是 生理T细胞刺激和无处不在的免疫反应研究潜伏期逆转和HIV动力学。 拟议的研究很重要，因为预计它将更好地理解相互作用 在适应性免疫和艾滋病毒持久性之间，将提供有关如何针对主要的新见解 HIV储层维护机制。最终，这种知识有可能提供新的知识 制定创新策略诱发艾滋病毒缓解的机会。