Enhancing Susceptibility of HIV Reservoirs to CTL Through a Discovery to Translational Approach

通过从发现到转化的方法增强 HIV 病毒库对 CTL 的易感性

• 批准号: 10676387
• 负责人: R. Brad Jones
• 金额: $ 86.22万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-24 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676387
• 关键词: Adherence; Anti-Retroviral Agents; Antigens; Area; Automobile Driving; BCL1 Oncogene; Biological Assay; Biological Process; CD4 Positive T Lymphocytes; CRISPR screen; Cell Death; Cell Survival; Cells; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Cytotoxic T-Lymphocytes; Data; Data Set; Epidemic; Essential Genes; Exposure to; Expression Profiling; Foundations; Freedom; Genes; Granzyme; HIV; HIV Infections; HIV resistance; Health Benefit; Immune Targeting; Immune response; Immune system; Immunooncology; Immunotherapy; In Vitro; Infection; Inflammation; Knock-out; Leadership; Mediating; Membrane Proteins; Modernization; Molecular; Outcome; Pathway interactions; Persons; Pharmaceutical Preparations; Play; Population; Predisposition; Productivity; Property; Public Health; Publishing; RNA Interference; Reporting; Resistance; Screening Result; Seminal; Series; Testing; Therapeutic; Toxic effect; Transcript; Validation; Viral; Virus; antagonist; antiretroviral therapy; cell killing; cell type; comorbidity; genome-wide; immunogenic; improved; in vivo; inhibitor; innovation; loss of function; mouse model; neoplastic cell; new therapeutic target; novel therapeutic intervention; overexpression; pre-clinical; preclinical evaluation; protein expression; protein profiling; research clinical testing; resistance mechanism; small molecule inhibitor; social stigma; success; synergism; therapeutic candidate; therapeutic target; tool; transcriptomics; translational approach; tumor

PROJECT SUMMARY/ABSTRACT Although modern antiretroviral (ARV) therapies have dramatically improved the outlooks for people living with HIV, they are unable to cure infection. For people with HIV a cure would represent freedom from many burdens, including stigma, expensive medications, and inflammation-associated co-morbidities. A cure would also have public health benefits, comprising a powerful tool to help end the HIV epidemic. Developing a cure for HIV requires developing an understanding of how the virus persists for years and decades in people, even when new rounds of cellular infection (replication) are blocked by ARVs, and despite the ongoing presence of antiviral immune responses. The dominant paradigm has been that the virus hides in a latent state in infected cells and is thus invisible to immune responses. Efforts to cure infection have therefore focused on therapeutically reversing HIV latency to expose these cells to elimination but have thus far yielded disappointing results. This, along with several converging lines of evidence, have led to more recent hypothesis that hiding from the immune system may not be the only mechanism by which HIV persists – but rather that these rare populations of infected cells may have been selected for those that possess cell-intrinsic resistance to killing by cytotoxic T-lymphocytes, even when they express antigen and are seen. This parallels recent findings from ImmunoOncology where it has now been well established that some immunogenic tumors undergo selection for cell-intrinsic resistance to CTL. For this project, we have assembled a team comprising a pioneer in establishing mechanisms of CTL resistance in tumors, and two HIV experts who have advanced the idea of CTL resistance in this setting through a series of ex vivo studies. By merging these areas of expertise, we Aim to comprehensively describe mechanisms of CTL resistance in HIV-infected primary CD4+ T-cells and to discern which of these are at play in real HIV reservoir cells from people with HIV. We will build from these results to select therapeutic targets and identify combination approaches that integrate these with HIV-specific CTL and latency reversal strategies to achieve specific elimination of HIV reservoir-harboring cells ex vivo. We will also leverage an innovative mouse model to test whether engaging these therapeutic targets limits the seeding of HIV reservoirs in vivo. The results of this project are thus expected to be: i) laying a broad foundation for understanding CTL resistance in the HIV reservoir and ii) pre-clinical validation of multiple therapeutic targets with the potential to contribute to a cure for HIV.

项目摘要/摘要 尽管现代的抗逆转录病毒（ARV）疗法已经显着改善了与之相处的人的前景 艾滋病毒，他们无法治愈感染。对于患有艾滋病毒治愈的人来说，可以代表许多伯恩斯的自由， 包括污名，昂贵的药物和与炎症相关的合并症。治愈也会有 公共卫生益处，完成了一种强大的工具，以帮助结束艾滋病毒流行病。开发艾滋病毒治疗 需要对病毒在人们的数年和数十年中如何持续数十年来建立了解，即使是新的 细胞感染（复制）的回合被ARV阻塞，并持续存在抗病毒 免疫反应。主要的范式是该病毒隐藏在受感染细胞和 因此，免疫反应是看不见的。因此，治愈感染的努力已集中在热中 逆转艾滋病毒潜伏期以使这些细胞暴露于进化，但到目前为止产生了令人失望的结果。这， 除了几条融合的证据外，还导致了最近的假设，即隐藏了免疫 系统可能不是艾滋病毒持续存在的唯一机制，而是这些罕见的感染人群 可能已经为具有细胞中性抗性的细胞毒性T-淋巴细胞杀死的人选择了细胞 即使它们表达抗原并被看到。这与免疫学的最新发现相似 现在已经有充分的确定，某些免疫原性肿瘤接受了细胞内抗性的选择 CTL。对于这个项目，我们召集了一个团队，完成了建立CTL机制的先驱 肿瘤的抵抗和两名在这种情况下通过 一系列的离体研究。通过合并这些专业领域，我们旨在全面描述 HIV感染的原发性CD4+ T细胞中CTL抗性的机制，并辨别其中哪种在 来自艾滋病毒患者的真正艾滋病毒储量细胞。我们将从这些结果中构建，以选择治疗目标和 确定将这些方法与HIV特异性CTL和潜伏期相结合的组合方法逆转策略 实现特异性消除HIV储层 - 养成的细胞。我们还将利用创新的鼠标 模型测试与这些治疗靶标合作是否限制了体内HIV储层的播种。结果 因此，该项目的预期为：i）为了解艾滋病毒中的CTL抗性奠定了广泛的基础 储层和II）对多个治疗靶标进行临床前验证，有可能有助于治疗 艾滋病病毒。