Formation of the HIV-1 Latent Reservoir

HIV-1 潜伏库的形成

• 批准号: 10013718
• 负责人: Ronald I Swanstrom
• 金额: $ 65.93万
• 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/10013718
• 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 最近，人们重新定义了HIV-1潜伏期的性质。我们最近的研究表明，大量的 大多数储存库(平均70%)是在治疗开始时形成的，可能是在治疗开始时形成的。这 是对储集层的一种非常不同的看法，而历史上的储集层是在早期之后开始形成的 感染并不断形成。抑制病毒复制会改变宿主环境，从而允许某些 细胞，其中一些被感染，变得更长的寿命。我们也证明了这对病毒DNA也是正确的 尽管其中大部分是有缺陷的。因此，潜伏的储存库标志着一组细胞过渡到长期存活的 无论他们的感染状况如何，他们都处于开始治疗的状态。这种潜在储集层的新观点令人难以接受 此应用程序中解决了许多关键问题。首先，如果在不同的 它的形成方式有相同的历史吗？我们将通过寻找两种替代方案来解决这个问题 潜伏宿主的定义：在停止治疗期间反弹的病毒，以及假定的“深”宿主 在肠道和淋巴组织中都有。第二，由于我们最初的观察是在一群女性中进行的，我们 会问同样的问题，关于男性体内储藏形成的时间。第三，自开始治疗以来 确定大多数储油层形成的时间，我们将检查储油层是否中断，并 在一段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 T细胞的分化状态，该T细胞含有在启动之前早期形成的储存库的子集 心理治疗。第五，我们将跟踪携带病毒的细胞的分化状态，这些病毒将形成长期存活的 蓄水池作为治疗方法抑制病毒复制。总而言之，这些研究将完成我们对 当水库形成时，无论人们如何定义水库，无论是男性还是女性。他们还将 在重新引入炎症状态后显示出水库的稳定性，而炎症状态之前在很大程度上阻止了 储层的形成。最后，他们将开始探索T细胞的分化状态，这些T细胞形成 早期病毒的蓄积和细胞因子环境面临病毒复制，然后处于分化状态 在抑制治疗期间，这些T细胞转变为长寿储存库的一部分。这些研究将提供 未来新策略的概念性框架，以在治疗开始时限制油藏的形成。