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: 10219055
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219055
• 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; 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; 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 Replication; Work; antiretroviral therapy; base; cell fixation; cohort; cytotoxic CD8 T cells; 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，使这些人背负着沉重的负担 终生致力于昂贵的抗逆转录病毒药物。也已经清楚的是 这些治疗方法并不能完全恢复健康，也不能解决负面的社会问题 与艾滋病毒呈阳性相关的问题。开发安全有效的艾滋病毒 因此，治愈将极大地改善感染者的生活。治愈艾滋病毒的主要障碍 感染是隐藏或“潜伏”病毒储存库的建立，这些病毒可以逃避 如果一个人停止抗逆转录病毒治疗，免疫系统可能会重新传播感染。 目前正在努力清除这些艾滋病毒储存库。理论上有 通过结合能够暴露隐藏的“延迟逆转代理”（LRA）可以实现 具有免疫效应器（例如杀伤性 T 细胞）的病毒，然后可以消除这些细胞， 所谓的“震惊和杀戮”方法。电击杀戮策略的可行性 得到使用潜伏期细胞系模型的体外实验的支持，其中组合 具有杀伤性 T 细胞的 LRA 可以减少 HIV 病毒库。然而，临床试验已 尝试在体内实现这一目标却取得了令人失望的结果。在初步 研究中，我们试图通过确定 LRA 的组合是否可以弥补这一差距 与杀伤性 T 细胞一起使用可以在体外消除患者 CD4+ T 细胞样本中的 HIV。我们做了 令人惊讶的观察结果是，这始终导致消除了 有缺陷的 HIV 前病毒构成了 HIV DNA 的大部分，但不影响 需要消除以治愈感染的完整诱导型原病毒。在当前 在该项目中，我们建议测试 HIV 特异性杀伤 T 细胞的不同组合， 本次检测中的 LRA，希望能够识别出能够更多地发挥作用的组合。 有效地靶向完整的诱导型原病毒。我们的研究设计将使我们能够确定 杀伤 T 细胞和 LRA 的一般特征与有效 消除完整的诱导型原病毒。在扰乱这些天然艾滋病毒的过程中 储层，我们还将测试各种储层测量分析以确定 最能反映完整诱导型原病毒与总/缺陷型原病毒的消耗 原病毒。因此，我们的研究将为设计提供关键指导 旨在在未来的临床试验中治愈艾滋病毒感染的干预措施，以及选择 以及这些研究中使用的储层测量分析的解释。