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 HIV-1潜在储层的性质最近被重新定义。我们最近的工作表明了一个大型 大多数储层（平均70％）是在治疗开始的附近，大概是在治疗开始的。这 与历史储备相比，水库的观点截然不同。 感染和形式不断。病毒复制的抑制会改变主机环境，以允许某些 细胞（其中一些被感染）长期存在。我们还表明，即使病毒DNA也是如此 虽然大多数都是有缺陷的。因此，潜在储层正在标记一组过渡到长寿的单元 无论其感染状况如何，都可以启动治疗。这种潜在水库的新观点 本应用程序中解决的许多关键问题。首先，如果储层是在不同的 它的形成方式有相同的历史吗？我们将通过查看两个替代方案来解决这个问题 潜在储层的定义：终止治疗期间的反弹病毒和推定的“深”水库 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，我们 会问关于男性水库形成时机的同样问题。第三，自治疗启动以来 确定何时形成大部分储层，我们将检查储层是否被破坏，并且 在毒品假期的一段时间内进行的改革，然后进行治疗重新生效。第四，我们将确定 T细胞的分化状态具有藏有储层子集的T细胞，该储层在启动之前早期形成 治疗。第五，我们将遵循具有长期寿命的病毒的细胞的分化状态 储层作为治疗抑制病毒复制。这些研究集体将完成我们对 当储层形成时，无论人们如何定义水库，无论是男人还是女人。他们也会 在重新引入以前预防的炎症状态后，显示了储层的稳定性 水库的形成。最后，他们将开始探索形成的T细胞的分化状态 面对病毒复制的早期储层和细胞因子环境，然后是分化状态 这些T细胞在抑制性治疗期间转变为长寿命储层的一部分。这些研究将提供 未来在治疗开始时限制储层形成的新策略的概念框架。