Treg in HIV-1 Replication and Pathogenesis

项目描述（由申请人提供）：该项目的目标是阐明FoxP3+CD4+CD25+天然Treg细胞在HIV-1复制和发病机制中的作用。Treg细胞水平在HIV-1疾病中的调节尚不清楚。关于Treg细胞在HIV感染和发病机制中的作用，我们所知的就更少了。Treg在HIV感染/发病机制中的混淆至少有以下原因：1)由于缺乏相关模型，Treg细胞在人体内的基本免疫生物学（发育、表型和功能）研究较少；2)大多数研究分析的血液中的Treg细胞可能不能反映淋巴组织中的大部分Treg细胞；3) Treg细胞在HIV不同疾病阶段受到的影响不同；4)研究人群内部和之间的年龄和遗传个体差异。迫切需要一个强大的动物模型来解决这些局限性，以研究Treg细胞在HIV感染中的调节和作用。DKO-hu HSC模型非常适合这一目的。我们可以用单个人胎儿肝供体组织（20-40只DKO-hu小鼠/供体FL组织）产生大的“近交”DKO-hu小鼠群体。具有稳定功能的人体免疫系统，DKO- hu小鼠各淋巴器官中FoxP3+CD4+ Treg细胞的发育比例正常。HIV-1建立持续感染，具有特异性免疫反应，免疫过度激活和人类CD4 T细胞耗竭。我假设急性HIV感染期间淋巴器官募集或诱导Treg细胞调节免疫反应。这些CD4+ Treg细胞也是很好的HIV靶细胞，支持高水平的HIV复制。在艾滋病进展期间的慢性HIV感染或致病性HIV变异的出现可能损害/耗尽功能性Treg细胞，导致超免疫激活和艾滋病进展。本项目将研究FoxP3+ Treg细胞在体内HIV-1感染、复制和发病机制中的作用。首先，我们将研究不同年龄DKO-hu小鼠体内淋巴组织Treg细胞的发育、功能和维持及其在自身耐受中的作用。其次，我们将研究HIV-1感染如何影响体内FoxP3+ Treg细胞的数量和功能。我们将确定HIV-1如何感染和影响淋巴组织中Treg细胞的增殖和存活。第三，我建议通过在HIV-1慢性感染之前或期间在DKO-hu HSC小鼠中增加或减少Treg细胞来测试Treg细胞在感染早期和HIV疾病进展慢慢性阶段的作用。该建议是基于我们广泛的初步结果和我们在相关模型中研究T细胞和HIV发病机制的既定经验。最重要的是，新型DKO-hu小鼠提供了第一个在体内直接研究人类Treg细胞在HIV感染过程中的功能和作用的小鼠模型。我们将重点关注Treg细胞在HIV感染和发病机制中的最基本问题。阐明HIV-1与FoxP3+ Treg细胞相互作用的机制及其在HIV-1感染和艾滋病发病中的作用将有助于我们了解HIV-1感染及其发病机制。这一发现不仅有助于我们了解Treg生物学在HIV感染和发病机制中的作用，而且有助于开发新的治疗方法。公共卫生相关性：我们将研究Treg细胞如何调节HIV感染及其发病机制的最基本问题。阐明HIV-1与FoxP3+ Treg细胞相互作用的机制及其在HIV-1感染和艾滋病发病中的作用将有助于我们了解HIV-1感染及其发病机制。这一发现不仅有助于我们了解Treg生物学在HIV感染和发病机制中的作用，而且有助于开发新的治疗方法。

DESCRIPTION (provided by applicant): The goals of the project are to elucidate the role of FoxP3+CD4+CD25+ natural Treg cells in HIV-1 replication and pathogenesis. The modulation of Treg cell levels in HIV-1 diseases is poorly understood. Even less is known about the role of Treg cells in HIV infection and pathogenesis. The confusion of Treg in HIV infection/pathogenesis is due to at least the following reasons: 1) Basic immuno-biology (development, phenotypes, and function) of Treg cells in human is poorly investigated due to lack of relevant models; 2) Treg cells from blood as analyzed in most studies may not reflect the majority of Treg cells in lymphoid tissues; 3) Treg cells may be affected differently at different HIV disease stages; and 4) individual difference in age and genetics within and between study populations. A robust animal model that addresses these limitations is urgently needed to study the modulation by, and role of Treg cells in, HIV infection. The DKO-hu HSC model is well-suited for this purpose. We can generate large "inbred" cohorts of DKO-hu mice with individual human fetal liver donor tissues (20-40 DKO-hu mice/donor FL tissue). With a stable functional human immune system, functional FoxP3+CD4+ Treg cells are developed in normal proportion in all lymphoid organs in DKO- hu mice. HIV-1 establishes persistent infection, with specific immune responses, immune hyperactivation and depletion of human CD4 T cells. I hypothesize that Treg cells are recruited or induced in lymphoid organs during acute HIV infection to modulate immune responses. These CD4+ Treg cells are also good HIV target cells that support high levels of HIV replication. Chronic HIV infection during AIDS progression or emergence of pathogenic HIV variants may impair/deplete functional Treg cells, leading to hyper-immune activation and AIDS progression. This project will investigate the role of FoxP3+ Treg cells in HIV-1 infection, replication and pathogenesis in vivo. First, we will study the development, function and maintenance of Treg cells in lymphoid tissues in vivo at different ages of DKO-hu mice, and their role in self tolerance. Second, we will study how HIV-1 infection affects number and function of FoxP3+ Treg cells in vivo. We will determine how HIV-1 infects and affects the proliferation and survival of Treg cells in lymphoid tissues. Third, I propose to test the role of Treg cells in early phase of infection and during chronic phased of HIV disease progression, by increasing or decreasing Treg cells in DKO-hu HSC mice before or during HIV-1 chronic infection. The proposal is based on our extensive preliminary results and our established experience in studying T cells and HIV pathogenesis in relevant models. Most importantly, the novel DKO-hu mouse has provided the first mouse model to directly investigate the function and role of human Treg cells during HIV infection in vivo. We will focus on the most fundamental questions of Treg cells in HIV infection and pathogenesis. Elucidation of the mechanism by which HIV-1 interacts with FoxP3+ Treg cells and their role in HIV-1 infection and AIDS pathogenesis will help us understand HIV-1 infection and pathogenesis. The findings will facilitate not only our understanding of Treg biology in HIV infection and pathogenesis, but also development of novel therapeutics. PUBLIC HEALTH RELEVANCE: We will investigate the most fundamental questions of how Treg cells modulate HIV infection and pathogenesis. Elucidation of the mechanism by which HIV-1 interacts with FoxP3+ Treg cells and their role in HIV-1 infection and AIDS pathogenesis will help us understand HIV-1 infection and pathogenesis. The findings will facilitate not only our understanding of Treg biology in HIV infection and pathogenesis, but also development of novel therapeutics.