Formation of the HIV-1 Latent Reservoir

HIV-1 潜伏库的形成

• 批准号: 10552552
• 负责人: Ronald I Swanstrom
• 金额: $ 57.42万
• 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/10552552
• 关键词: Address; Antigens; Antiviral Therapy; Apoptosis; Archives; Award; Behavior; Biological; Blood; Blood Cells; CD4 Positive T Lymphocytes; Cells; Clinical; Collaborations; Collecting Cell; 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; 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潜伏库的性质最近被重新定义。我们最近的研究表明， 大部分储库（平均70%）在治疗开始时形成，并且可能在治疗开始时形成。这 是一个非常不同的看法水库从历史上的一个水库开始形成后， 感染，并不断形成。病毒复制的抑制改变了宿主环境， 细胞，其中一些被感染，变得长寿。我们还证明了这对病毒DNA也是如此， 虽然大部分都有缺陷因此，潜在的水库是标志着一组细胞过渡到长寿 开始治疗时的状态，无论其感染状态如何。这种关于潜在储层的新观点 在本申请中解决的一些关键问题。首先，如果水库是在不同的 它的形成是否有着相同的历史？我们将通过两种选择来解决这个问题 潜伏性储库的定义：治疗中止期间病毒反弹，以及假定的“深层”储库 在肠道和淋巴结组织中。其次，由于我们最初的观察是在一组女性中进行的，我们 也会问同样的问题关于男性储层形成的时间。第三，自治疗开始以来， 确定大部分储层形成的时间，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 T细胞的分化状态，所述T细胞具有在免疫启动之前早期形成的储库的亚群。 疗法第五，我们将跟踪携带病毒的细胞的分化状态， 储库作为治疗抑制病毒复制。总的来说，这些研究将使我们对 当水库形成时，无论人们如何定义水库，在男性和女性中。他们还将 显示了在重新引入先前在很大程度上阻止了的炎症状态后， 水库的形成。最后，他们将开始探索形成T细胞的分化状态。 早期水库和细胞因子环境面临病毒复制，然后分化状态 在抑制治疗期间，这些T细胞转变为长效储存库的一部分。这些研究将提供 一个概念框架，为未来的新策略，以限制水库形成时，治疗开始。