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: 10253391
• 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/10253391
• 关键词: Achievement; Address; Anti-Retroviral Agents; Antifungal Agents; Antigens; Automobile Driving; Award; CD4 Positive T Lymphocytes; Candida; Candida albicans; Caring; Cell Survival; Cell division; Cells; Chronic; Clinical; Clonal Expansion; Clone Cells; Collaborations; Communication; Cytomegalovirus; DNA; Decision Making; 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; Lead; Learning; Life; Maintenance; Measures; Medicine; Mentors; Mission; Morbidity - disease rate; National Cancer Institute; National Institute of Allergy and Infectious Disease; Outcome; Paper; Pathogenicity; Pennsylvania; Pharmaceutical Preparations; Physiological; Play; Population; Postdoctoral Fellow; Prevention; Principal Investigator; Process; Proliferating; Proteins; Public Health; Publishing; Research; Role; Running; Schools; 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; commensal microbes; design; effective intervention; experience; experimental study; immune clearance; in vivo; innovation; insight; interest; 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.

项目概要 抗逆转录病毒疗法（ART）大大降低了艾滋病毒的发病率和死亡率。但对艾滋病毒没有作用 储存库，一小群潜伏感染的细胞，在治疗中断时会重新引发感染。由于 由于该病毒库的持续存在，必须无限期地继续抗逆转录病毒治疗，这需要公共卫生系统提供 为所有 3800 万艾滋病毒感染者提供终身药物治疗。该研究计划的长期目标是 帮助开发新的治疗方法来消除或控制艾滋病毒储存库，从而实现无药物治疗 缓解。受感染细胞的增殖是 HIV 持续存在的一个主要机制，因为它会导致病毒感染扩大 携带原病毒 DNA 的 CD4+ T 细胞克隆。最近的研究表明，抗原特异性免疫反应 很大程度上促成了这一现象。该应用程序的总体目标是了解慢性病的作用 抗原决定构成HIV病毒库的克隆的结构和动态。底层的 中心假设是适应性免疫反应对 HIV 感染细胞施加选择性压力。这 该项目的基本原理是，如果克隆扩增是艾滋病毒持续存在的主要机制之一，那么针对 这一过程将减小储层的尺寸并加速其腐烂。中心假设将被检验 追求三个具体目标：1）确定抗原对 HIV 潜伏期逆转的影响； 2）确定因素 负责HIV感染的抗原特异性克隆的扩增和维持； 3) 确定 共生病原体的慢性抗原在驱动储存库持续存在中的作用。第一个目标下，CD4+ 将分离对巨细胞病毒（CMV，导致常见慢性感染的病毒）有反应的 T 细胞 来自 HIV 感染者并进行离体扩增。用同源 CMV 抗原、HIV 刺激 T 细胞后 潜伏期将在单细胞水平上进行研究，并与非特异性最大 T 细胞刺激进行比较，通常 用于在体外逆转潜伏期。对于第二个目标，将追踪携带 HIV 的 CMV 反应性克隆 在引入 ART 期间对具有 CMV 复制的个体进行纵向研究，以努力了解 其扩张背后的事件。第三个目标是白色念珠菌，一种致病性共生酵母， 在驱动抗真菌免疫反应中发挥重要作用，将用于证明长期暴露是否 共生微生物塑造了 CD4+ T 细胞的所有组成部分，包括 HIV 储存库的那些部分。这 本申请提出的研究具有创新性，因为与现状相比，它侧重于 生理性 T 细胞刺激和无处不在的免疫反应，以研究潜伏期逆转和 HIV 动态。 拟议的研究意义重大，因为它有望更好地理解相互作用 适应性免疫和艾滋病毒持续性之间的关系，并将为如何针对主要的目标提供新的见解 HIV储存库维持机制。最终，这些知识有可能提供新的知识 制定诱导艾滋病毒缓解的创新策略的机会。