CTL-Mediated Elimination of Replication Competent vs. Defective HIV Proviruses from Natural Latent Reservoirs: Roles of Antigen Specificity and Functional Characteristics

CTL介导从天然潜伏病毒库中消除复制能力与缺陷型HIV原病毒：抗原特异性和功能特征的作用

• 批准号: 9766182
• 负责人: R. Brad Jones
• 金额: $ 42.38万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766182
• 关键词: AIDS/HIV problem; Address; Adherence; Anatomy; Anti-Retroviral Agents; Antigen Targeting; Antigens; Autologous; Automobile Driving; Avidity; Biological Assay; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Line; Cells; Characteristics; Clinical; Clinical Trials; Clone Cells; Consensus; Cytotoxic T-Lymphocytes; DNA; Data; Development; Dimensions; Effectiveness; Epitopes; Future; Granzyme; HIV; HIV Infections; HIV Seropositivity; Health; Health Services Accessibility; Immune; Immune system; Immunologics; In Vitro; Individual; Infection; Intervention; Latent Virus; Lymphoid Follicle; Measurement; Mediating; Modeling; Modernization; Mosaicism; Mutation; Outcome; Participant; Patients; Peptide Library; Peptides; Pharmaceutical Preparations; Phenotype; Play; Population; Process; Proteins; Proteome; Proviruses; Regimen; Research Design; Role; Sampling; Seeds; Shock; Specificity; T cell response; T-Lymphocyte; Testing; Viral; Viral reservoir; Viremia; Virus; Virus Latency; Virus Replication; Work; antiretroviral therapy; base; cell fixation; cohort; cytotoxicity; exhaustion; experimental study; functional disability; improved; in vivo; pandemic disease; perforin; purge; response; social; therapy design; therapy development; tool; viral rebound; virology

Although modern therapies have improved the outlooks for people living with HIV/AIDS (PLWHA) they are unable to cure infection, leaving these individuals burdened by a lifelong commitment to expensive antiretroviral medication. It has also become clear that these treatments do not fully restore health, nor do they address the negative social issues associated with being HIV positive. The development of a safe and effective HIV cure would thus greatly improve the lives of PLWHA. A major obstacle to curing HIV infection is the establishment of reservoirs of hidden or ‘latent’ virus which evade the immune system and can re-seed infection if an individual stops antiretroviral therapy. Efforts are underway to attempt to purge these HIV reservoirs. There is theoretically achievable by combining ‘latency reversing agents’ (LRAs) capable of exposing hidden virus with immune effectors such as killer T-cells that can then eliminate these cells, the so-called ‘shock and kill’ approach. The viability of the shock and kill strategy is supported by in vitro experiments using cell line models of latency, where combinations of LRAs with killer T-cells can reduce HIV reservoirs. However, clinical trials that have attempted to achieve this in vivo have yielded disappointing results. In preliminary studies, we have attempted to bridge this gap by determining if combinations of LRAs with killer T-cells could eliminate HIV from patient CD4+ T-cell samples in vitro. We made the surprising observation that this consistently resulted in the elimination of the defective HIV proviruses that make up the majority of HIV DNA, without impacting the intact inducible proviruses that need to be eliminated to cure infection. In the current project we propose the testing of different combinations of HIV-specific killer T-cells and LRAs in this assay, in the hopes of identifying combinations that are able to more effectively target intact inducible proviruses. Our study design will allow us to identify general features of both killer T-cells and of LRAs that are associated with effective elimination of intact inducible proviruses. In the process of perturbing these natural HIV reservoirs, we will also test a wide range of reservoir measurement assays to determine which best reflect depletions in intact inducible proviruses versus of total/defective proviruses. Our study will thus provide critical guidance both for the design of interventions aimed at curing HIV infection in future clinical trials, and for the selection and interpretation of reservoir measurement assays to be used in these studies.

尽管现代疗法改善了艾滋病毒/艾滋病患者的前景 （plwha）他们无法治愈感染，使这些人被一个 终身致力于昂贵的抗逆转录病毒药物。也很清楚 这些治疗方法无法完全恢复健康，也无法解决负面的社会 与艾滋病毒呈阳性有关的问题。安全有效的艾滋病毒的发展 因此，治愈将大大改善PLWHA的生活。治愈艾滋病毒的主要障碍 感染是建立隐藏或“潜在”病毒的储量 免疫系统，如果一个人停止抗逆转录病毒疗法，可以重新种植感染。 正在努力清除这些艾滋病毒水库。有理论 通过结合“延迟逆转剂”（LRA）可以实现的实现 具有免疫作用的病毒，例如杀手T细胞，然后可以消除这些细胞， 所谓的“震惊与杀戮”方法。冲击和杀戮策略的可行性是 使用潜伏的细胞系模型在体外实验中支持，其中组合 带有杀手T细胞的LRA可以减少艾滋病毒水库。但是，具有 试图在体内实现这一目标的结果令人失望。在初步 研究，我们试图通过确定LRA的组合来弥合这一差距 使用杀手T细胞可以在体外从患者CD4+ T细胞样品中消除HIV。我们做了 令人惊讶的观察结果是，这始终导致消除 构成大多数HIV DNA的HIV病毒缺陷，而不会影响 需要消除以治愈感染的完整诱导病毒。在电流中 项目我们建议对艾滋病毒特异性杀手T细胞的不同组合进行测试 在该测定中的LRA，希望识别能够更多的组合 有效地靶向完整的诱导性病毒。我们的研究设计将使我们能够确定 杀手T细胞和与有效相关的LRA的一般特征 消除完整的诱导性病毒。在扰动这些天然艾滋病毒的过程中 水库，我们还将测试广泛的储层测量测定法以确定 最好反映完整诱导的病毒的耗尽与总/缺陷 因此，我们的研究将为设计提供关键指导 旨在在将来的临床试验中治愈HIV感染的干预措施以及选择 以及这些研究中要使用的储层测量测定法的解释。