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，使这些人背负着沉重的负担。 终身服用昂贵的抗逆转录病毒药物。也显示 这些治疗不能完全恢复健康，也不能解决负面的社会问题。 与HIV阳性相关的问题。开发安全有效的艾滋病毒 因此，治疗将大大改善艾滋病毒/艾滋病感染者的生活。治愈艾滋病的主要障碍 感染是建立隐藏或“潜伏”病毒的水库， 如果停止抗逆转录病毒治疗，可能会重新引发感染。 目前正在努力清除这些艾滋病毒储存库。理论上 通过结合能够暴露隐藏的“延迟逆转代理”（LRA） 病毒与免疫效应器，如杀伤T细胞，然后可以消除这些细胞， 即所谓的“震慑和杀死”方法。休克和杀死战略的可行性是 得到了使用潜伏期细胞系模型的体外实验的支持，其中组合 LRA与杀伤性T细胞可以减少艾滋病病毒库。然而，临床试验， 试图在体内实现这一目标的结果令人失望。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， 用杀伤T细胞可以在体外从患者CD 4 + T细胞样品中消除HIV。我们做 令人惊讶的观察是，这一直导致消除了 有缺陷的艾滋病毒前病毒，构成了艾滋病毒DNA的大部分，而不影响 完整的可诱导前病毒，需要被消除以治愈感染。在当前 我们建议测试艾滋病毒特异性杀伤T细胞的不同组合， LRA在这项试验中，希望确定的组合，能够更多地 有效靶向完整的诱导型前病毒。我们的研究设计将使我们能够识别 杀伤T细胞和LRA的一般特征与有效的 消除完整的诱导型前病毒。在扰乱这些自然的艾滋病毒的过程中 我们还将测试各种储层测量分析，以确定 其最好地反映了完整的诱导型前病毒相对于全部/缺陷型前病毒的消耗， 前病毒因此，我们的研究将为设计 干预措施，旨在治愈艾滋病毒感染在未来的临床试验，并为选择 以及解释这些研究中使用的储层测量分析。