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: 10488649
• 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/10488649
• 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; Persons; 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.

项目总结 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。然而，它对艾滋病毒没有任何影响。 蓄水池，一个小的潜伏感染细胞池，一旦治疗中断，就会重新引发感染。由于 这种蓄水池的持久性，必须无限期地继续下去，要求公共卫生系统提供 向所有3800万艾滋病毒携带者终身提供药物。这项研究计划的长期目标是 帮助开发新的治疗方法以消除或控制艾滋病毒携带者，导致无药物 减刑。受感染细胞的增殖是艾滋病毒持续存在的主要机制，因为它导致了 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 这在很大程度上促成了这一现象。本应用程序的总体目标是了解慢性疾病的作用 抗原在确定构成艾滋病毒储存库的克隆的结构和动力学方面的作用。潜在的 中心假设是获得性免疫反应对感染艾滋病毒的细胞施加选择性压力。这个 该项目的基本原理是，如果克隆扩张是艾滋病毒持续存在的主要机制之一，靶向 这一过程将缩小水库的大小，并加速其腐烂。核心假设将通过以下方式进行检验 追求三个具体目标：1)确定抗原对HIV潜伏期逆转的影响；2)确定影响因素 负责扩展和维护感染艾滋病毒的抗原特异性克隆；以及3)确定 共生病原体慢性抗原在驱动储集层持久性中的作用在第一个目标下，CD4+ 将分离对巨细胞病毒(CMV，一种导致常见慢性感染的病毒)产生反应的T细胞 来自艾滋病毒携带者和体外扩大的人。用同源巨细胞病毒抗原刺激T细胞时，HIV 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 用于逆转体外潜伏期。对于第二个目标，将跟踪携带艾滋病毒的巨细胞病毒反应克隆 在ART引入前后纵向上复制了CMV的个体，以努力理解 它们扩张背后的事件。对于第三个目的，白色念珠菌，一种致病共生酵母， 在驱动抗真菌免疫反应方面起着主要作用，将被用来证明慢性暴露 共生微生物塑造了CD4+T细胞的保存库，包括那些HIV储存库的部分。这个 本申请中提出的研究具有创新性，因为与现状相比，它侧重于 生理T细胞刺激和无处不在的免疫反应，以研究潜伏期逆转和艾滋病毒动力学。 这项拟议的研究意义重大，因为它有望导致对相互作用的更好理解 获得性免疫和艾滋病毒持久性之间的关系，并将为如何针对主要 HIV储备库的维护机制。归根结底，这种知识有可能提供新的 发展创新战略以促使艾滋病毒缓解的机会。