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 尽管现代抗逆转录病毒(ARV)疗法极大地改善了艾滋病患者的前景 艾滋病毒，他们无法治愈感染。对于艾滋病毒携带者来说，治愈意味着摆脱许多负担， 包括耻辱、昂贵的药物和炎症相关的共病。治愈方法也会有 公共卫生福利，这是帮助结束艾滋病毒流行的有力工具。开发一种治疗艾滋病毒的方法 需要发展对病毒如何在人身上持续多年和数十年的理解，即使是在新的 尽管持续存在抗病毒药物，但ARV阻止了几轮细胞感染(复制) 免疫反应。主导范式一直是病毒隐藏在受感染细胞中的潜伏状态，并 因此对免疫反应是不可见的。因此，治愈感染的努力集中在治疗上。 逆转艾滋病毒潜伏期使这些细胞被消灭，但迄今产生了令人失望的结果。这, 伴随着几条趋同的证据，导致了更新的假设，即躲避免疫 系统可能不是HIV持续存在的唯一机制--而是这些罕见的感染人群 细胞可能被选为对细胞毒性T淋巴细胞杀伤具有细胞固有抵抗力的细胞， 即使当它们表达抗原并被看到的时候。这与免疫肿瘤学最近的发现是一致的，在那里 现在已经很好地证实了一些免疫原性肿瘤经历了对细胞固有耐药性的选择 CTL.为了这个项目，我们组建了一个团队，其中包括建立CTL机制的先行者 肿瘤的耐药性，以及两位艾滋病毒专家，他们通过 一系列的体外研究。通过合并这些专业领域，我们的目标是全面描述 HIV感染的原代CD4+T细胞中CTL耐药的机制及其在其中的作用 来自艾滋病毒携带者的真正的艾滋病毒储存细胞。我们将根据这些结果来选择治疗靶点和 确定将这些与HIV特异性CTL和潜伏期逆转策略相结合的组合方法，以 在体外实现对携带艾滋病毒储存库的细胞的特异性消除。我们还将利用创新的鼠标 模型，以测试使用这些治疗靶点是否限制体内艾滋病毒储存库的播种。结果是 因此，这一项目的预期目标是：i)为了解艾滋病毒中CTL耐药性奠定广泛基础 蓄水池和II)多个治疗靶点的临床前验证，有可能有助于治愈 爱滋病毒。