Mechanisms of CTL Resistance in HIV Reservoirs

HIV病毒库中CTL耐药机制

• 批准号: 10669775
• 负责人: R. Brad Jones
• 金额: $ 80.05万
• 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/10669775
• 关键词: Adherence; Advanced Development; Agonist; Anti-Retroviral Agents; Applications Grants; Autologous; BCL1 Oncogene; Biological Assay; Biology; CD4 Positive T Lymphocytes; Candidate Disease Gene; Cell Culture Techniques; Cell Survival; 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; Enabling Factors; Future; Gene Expression Profiling; Genes; Genetic Transcription; Goals; Granzyme; HIV; HIV Infections; Health; Human; Immune system; Immunotherapy; Impairment; Individual; Infection; Intrinsic factor; 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; Technology; Testing; Therapeutic; Treatment Efficacy; Validation; Viral reservoir; Virus; Work; antagonist; antiretroviral therapy; arm; candidate identification; 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携带者的前景，但它们无法 为了治愈感染，这些人背负着终身服用抗逆转录病毒(ARV)药物的负担。 对于任何特定的个人来说，保持终生坚持服药可能会带来巨大的挑战。 此外，许多人无法获得这些昂贵的药物--特别是那些生活在 资源受限设置。因此，开发新的疗法将具有巨大的价值，这种疗法可以 治愈艾滋病毒感染或使其缓解(病毒水平保持在低水平或检测不到的状态 一个人停止服用抗逆转录病毒药物)。治愈或缓解的一种方法是重新激活潜伏期 (隐藏的)病毒的“蓄水池”，并利用免疫系统来减少或消除这些蓄水池。这些东西太棒了 &KILL的方法通常集中在细胞毒性T细胞(CTL)上，它是免疫系统的一只手臂，专门用于 清除受病毒感染的细胞。虽然“踢杀”策略在潜伏期的体外模型中显示出了希望，但它 在临床试验中尚未见效。在最近的工作中，我们发现了消除 通过显示HIV感染的细胞对CTL具有内在的抵抗力--即使当它们被迫 通过潜伏期反转剂(LRA)将病毒展示给免疫系统。尽管这种内在抵抗力的想法 在HIV的背景下，对CTL还没有被广泛考虑，它被认为是限制治疗的一个因素 对癌症的疗效。在这项拨款申请中，我们建议利用尖端技术来识别新的 靶细胞抵抗CTL清除的机制。这些方法预计将产生大量的 点击数，我们将对其执行高分辨率的机械特性化。然后我们会研究 从艾滋病毒携带者身上采集样本，以确定这些耐药机制中的哪一种在艾滋病毒中发挥作用 体内持久力。最后，我们将直接测试针对这种耐药性的疗法是否可以允许CTL杀死 这些体外储藏细胞。我们期望我们的研究结果将是对小说的识别 开发旨在治愈艾滋病毒感染或实现缓解的治疗方法的目标。更广泛地说，我们 预计这里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。