Formation of the HIV-1 Latent Reservoir

HIV-1 潜伏库的形成

• 批准号: 10343734
• 负责人: Ronald I Swanstrom
• 金额: $ 59.14万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-13 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10343734
• 关键词: Address; Antigens; Antiviral Therapy; Apoptosis; Archives; Award; Behavior; Biological; Blood; Blood Cells; CD4 Positive T Lymphocytes; Cells; Clinical; Collaborations; Data; Data Analyses; Emodin; Environment; Event; Funding; Future; Genome; HIV; HIV-1; Holidays; Individual; Infection; Inflammation; Inflammatory; International; Interphase Cell; Lymph Node Tissue; Lymphoid Tissue; Nature; North Carolina; Pattern; Pharmaceutical Preparations; Population Heterogeneity; Recording of previous events; Research; Rest; Sampling; South Africa; Sweden; T-Lymphocyte; T-Lymphocyte Subsets; Time; Tissues; United States National Institutes of Health; Universities; Veins; Viral; Viral reservoir; Virus; Virus Latency; Virus Replication; Woman; Work; antiretroviral therapy; base; cell type; clinical research site; cohort; cytokine; experience; insight; latent HIV reservoir; men; prevent; superinfection; viral DNA; viral rebound

PROJECT ABSTRACT The nature of the HIV-1 latent reservoir has recently been redefined. Our recent work has shown that a large majority of the reservoir (on average 70%) is formed near, and presumably at, the time of therapy initiation. This is a very different view of the reservoir from the historical one where the reservoir starts to be formed early after infection and forms continuously. Suppression of viral replication changes the host environment to allow certain cells, some of which are infected, to become long lived. We have also shown this is true for viral DNA even though most of it is defective. Thus, the latent reservoir is marking a set of cells that transition to a long-lived state with the initiation of therapy irrespective of their infection status. This new view of the latent reservoir begs a number of key questions that are addressed in this application. First, if the reservoir is defined in a different way does its formation have the same history? We will address this question by looking at two alternative definitions of the latent reservoir: rebound virus during therapy discontinuation, and a putative "deep" reservoir in both gut and lymph node tissue. Second, since our initial observations were made in a cohort of women, we will ask the same question about the timing of reservoir formation in men. Third, since the initiation of therapy determines when a majority of the reservoir is formed, we will examine whether the reservoir is disrupted and reforms over a period of a drug holiday followed by therapy re-initiation. Fourth, we will determine the differentiation state of the T cells harboring the subset of the reservoir that forms early prior to the initiation of therapy. Fifth, we will follow the differentiation state of cells harboring the viruses that will form the long-lived reservoir as therapy suppresses viral replication. Collectively these studies will complete our understanding of when the reservoir forms, regardless of how one defines the reservoir, in both men and women. They will also show the stability of the reservoir after reintroducing an inflammatory state that had previously largely prevented the formation of the reservoir. Finally, they will start to explore the differentiation state of the T cells that form the early reservoir and the cytokine environment present in the face of viral replication, then the differentiation state these T cells transition to as part of the long-lived reservoir during suppressive therapy. These studies will provide a conceptual framework for future new strategies to limit reservoir formation at the time of therapy initiation.

项目摘要 HIV-1 潜伏病毒库的性质最近被重新定义。我们最近的工作表明，大量 大部分储库（平均 70%）是在治疗开始时附近（大概是在治疗开始时）形成的。这 这是一种与历史观点截然不同的观点，历史观点认为水库是在 感染并不断形成。抑制病毒复制会改变宿主环境，以允许某些病毒复制 细胞（其中一些被感染）变得长寿。我们还表明，对于病毒 DNA 来说也是如此 虽然大部分都是有缺陷的。因此，潜在储存库正在标记一组转变为长寿命细胞的细胞。 开始治疗时的状态，无论其感染状况如何。这种关于潜在储层的新观点需要 本申请中解决了一些关键问题。首先，如果存储库定义在不同的 它的形成有相同的历史吗？我们将通过研究两种替代方案来解决这个问题 潜伏病毒库的定义：治疗中断期间病毒反弹，以及假定的“深层”病毒库 在肠道和淋巴结组织中。其次，由于我们最初的观察是在一群女性中进行的，因此我们 会问关于男性水库形成时间的相同问题。三、自治疗开始以来 确定大部分储层何时形成，我们将检查储层是否被破坏， 在药物假期期间进行改革，然后重新开始治疗。第四，我们将确定 含有储库子集的 T 细胞的分化状态，该子集在启动之前早期形成 治疗。第五，我们将跟踪携带病毒的细胞的分化状态，这些病毒将形成长寿细胞 储存库作为治疗抑制病毒复制。总的来说，这些研究将完善我们对 当储存库形成时，无论人们如何定义储存库，无论男性还是女性。他们还将 显示了在重新引入之前很大程度上阻止的炎症状态后储库的稳定性 水库的形成。最后，他们将开始探索形成 T 细胞的分化状态。 早期储存库和病毒复制时存在的细胞因子环境，然后是分化状态 在抑制治疗期间，这些 T 细胞转变为长寿命储存库的一部分。这些研究将提供 未来新策略的概念框架，以限制治疗开始时的储库形成。