Mechanisms of CTL Resistance in HIV Reservoirs

HIV病毒库中CTL耐药机制

• 批准号: 10548335
• 负责人: R. Brad Jones
• 金额: $ 81.2万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10548335
• 关键词: Adherence; Advanced Development; Agonist; Anti-Retroviral Agents; Applications Grants; Autologous; BCL2 gene; Biological Assay; Biology; CD4 Positive T Lymphocytes; Candidate Disease Gene; Cell Culture Techniques; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Cessation of life; Clinical Trials; Clone Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Coculture Techniques; Consultations; Cytotoxic T-Lymphocytes; Data; Disease remission; Dissection; EZH2 gene; Future; Gene Expression Profiling; Genes; Genetic Transcription; Goals; Granzyme; HIV; HIV Infections; Health; Human; Immune system; Immunotherapy; Impairment; Individual; Infection; Intrinsic factor; Lead; Letters; Leukapheresis; Literature; Malignant Neoplasms; Mediating; Microscopy; Modernization; Outcome; Pathway interactions; Persons; Pharmaceutical Preparations; Phenotype; Play; Predisposition; Reporting; Resistance; Resolution; Resource-limited setting; Resources; Role; Sampling; Sampling Studies; Serine Proteinase Inhibitors; Suggestion; Technology; Testing; Therapeutic; Time; Treatment Efficacy; Validation; Viral reservoir; Virus; Work; antagonist; antiretroviral therapy; arm; base; cell killing; cell type; differential expression; effector T cell; immune clearance; improved; in vitro Model; in vivo; insight; next generation sequencing; novel; novel therapeutics; overexpression; resistance factors; resistance gene; resistance mechanism; small molecule; targeted treatment; therapeutic candidate; therapeutic target; therapy development

PROJECT SUMMARY/ABSTRACT Although modern therapies have dramatically improved the outlooks for people living with HIV, they are unable to cure infection, leaving these individuals burdened by a lifelong commitment to antiretroviral (ARV) medication. For any given individual, maintaining lifelong adherence to medication can present substantial challenges. Moreover, many people do not have access to these expensive medications - in particular those living in resource-limited settings. It would therefore be of tremendous value to develop novel therapies that can either cure HIV infection or drive it into remission (a state where levels of virus remain low or undetectable even when one stops taking ARV medication). One approach to achieving either a cure or remission is to reactivate latent (hidden) ‘reservoirs’ of virus and harness the immune system to reduce or eliminate these reservoirs. These ‘kick & kill’ approaches often focus on cytotoxic T-cells (CTL), which are an arm of the immune system specialized in eliminating virus-infected cells. While the ‘kick & kill’ strategy has shown promise in in vitro models of latency, it has not yet been effective in clinical trials. In recent work, we have uncovered an additional barrier to eliminating viral reservoirs by showing that HIV-infected cells are intrinsically resistant to CTL - even when they are forced to show virus to the immune system by latency reversing agents (LRAs). Although this idea of intrinsic resistance to CTL has not been widely considered in the context of HIV, it is well known as a factor that limits therapeutic efficacy in cancer. In this grant application we propose to leverage cutting edge technologies to identify novel mechanisms by which target cells resist elimination by CTL. These approaches are expected to yield a large number of ‘hits’, for which we will perform high-resolution mechanistic characterizations. We will then study samples from people living with HIV to determine which of these mechanisms of resistance play roles in HIV persistence in vivo. Finally, we will directly test whether therapies targeting this resistance can allow CTL to kill these ex vivo reservoir-harboring cells. We expect that the outcome of our study will be the identification of novel targets for the development of therapies aimed at curing HIV infection or enabling remission. More broadly, we anticipate that the mechanisms identified here will provide fundamental insights into the biology of CTL with implications for cancer & other conditions.

项目摘要/摘要 尽管现代疗法极大地改善了艾滋病毒患者的前景，但他们无法 为了治愈感染，使这些人因对抗逆转录病毒（ARV）药物的终生承诺而燃烧。 对于任何给定的人，维持终身遵守药物可能会带来重大挑战。 此外，许多人无法使用这些昂贵的药物 - 特别是那些居住在 资源有限的设置。因此，开发可以 治愈艾滋病毒感染或将其驱逐到缓解（即使病毒水平保持低或无法检测到的状态 一个停止服用ARV药物）。实现治愈或缓解的一种方法是重新激活潜在 （隐藏的）病毒和利用免疫系统的“储层”，以减少或消除这些储层。这些'踢 ＆Kill’方法通常专注于细胞毒性T细胞（CTL），该方法是专门用于免疫系统的手臂 消除感染病毒的细胞。虽然“踢和杀戮”策略在体外延迟模型中表现出了希望，但 在临床试验中尚未有效。在最近的工作中，我们发现了消除的额外障碍 病毒储层通过表明感染HIV的细胞在本质上对CTL具有抗性 - 即使它们被迫 通过潜伏期逆转剂（LRA）向免疫系统展示病毒。虽然这种内在抵抗的想法 在HIV的背景下，CTL并未被广泛考虑，这是限制治疗的因素 癌症的功效。在此赠款应用中，我们建议利用尖端技术来识别新颖 靶细胞抵抗CTL消除的机制。这些方法有望产生大的 “命中”的数量，我们将执行高分辨率机械特征。然后我们将学习 来自艾滋病毒的人的样本以确定这些抗药性中的哪些机制在艾滋病毒中起着作用 体内持久性。最后，我们将直接测试针对这种抗性的疗法是否可以允许CTL杀死 这些离体储层 - 湖泊细胞。我们预计我们的研究结果将是新颖的识别 旨在治愈艾滋病毒感染或启用缓解的疗法的靶标。更广泛地说，我们 预计此处确定的机制将提供对CTL生物学的基本见解 对癌症和其他疾病的影响。