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
基本信息
- 批准号:9766182
- 负责人:
- 金额:$ 42.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:
项目摘要
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

暂无数据
数据更新时间:2024-06-01
R. Brad Jones的其他基金
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:1067638710676387
- 财政年份:2023
- 资助金额:$ 42.38万$ 42.38万
- 项目类别:
A participant-derived xenograft mouse model to study T-cell-mediated viral control and mRNA vaccine strategies
参与者衍生的异种移植小鼠模型,用于研究 T 细胞介导的病毒控制和 mRNA 疫苗策略
- 批准号:1048370310483703
- 财政年份:2022
- 资助金额:$ 42.38万$ 42.38万
- 项目类别:
Mechanisms of CTL Resistance in HIV Reservoirs
HIV病毒库中CTL耐药机制
- 批准号:1054833510548335
- 财政年份:2022
- 资助金额:$ 42.38万$ 42.38万
- 项目类别:
A participant-derived xenograft mouse model to study T-cell-mediated viral control and mRNA vaccine strategies
参与者衍生的异种移植小鼠模型,用于研究 T 细胞介导的病毒控制和 mRNA 疫苗策略
- 批准号:1068322110683221
- 财政年份:2022
- 资助金额:$ 42.38万$ 42.38万
- 项目类别:
Mechanisms of CTL Resistance in HIV Reservoirs
HIV病毒库中CTL耐药机制
- 批准号:1066977510669775
- 财政年份:2022
- 资助金额:$ 42.38万$ 42.38万
- 项目类别:
Characterization of a Memory CD4+ T-cell Humanized Mouse Model for the Evaluation of Autologous Cell Therapies and Studies of HIV Persistence
用于评估自体细胞疗法和 HIV 持久性研究的记忆 CD4 T 细胞人源化小鼠模型的表征
- 批准号:1024209310242093
- 财政年份:2020
- 资助金额:$ 42.38万$ 42.38万
- 项目类别:
Characterization of a Memory CD4+ T-cell Humanized Mouse Model for the Evaluation of Autologous Cell Therapies and Studies of HIV Persistence
用于评估自体细胞疗法和 HIV 持久性研究的记忆 CD4 T 细胞人源化小鼠模型的表征
- 批准号:1001367910013679
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BELIEVE: Bench to Bed Enhanced Lymphocyte Infusions to Engineer Viral Eradication
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- 批准号:99764449976444
- 财政年份:2018
- 资助金额:$ 42.38万$ 42.38万
- 项目类别:
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:1021905510219055
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BELIEVE: Bench to Bed Enhanced Lymphocyte Infusions to Engineer Viral Eradication
相信:从床到床增强淋巴细胞输注可实现病毒根除
- 批准号:97688859768885
- 财政年份:2018
- 资助金额:$ 42.38万$ 42.38万
- 项目类别:
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