Treg in HIV-1 Replication and Pathogenesis

描述（由申请人提供）：该项目的目的是阐明FoxP 3 + CD 4 + CD 25+天然Treg细胞在HIV-1复制和发病机制中的作用。调节HIV-1疾病中的Treg细胞水平知之甚少。对Treg细胞在HIV感染和发病机制中的作用知之甚少。Treg在HIV感染/发病机制中的混淆至少是由于以下原因：1）基础免疫生物学由于缺乏相关模型，对人中Treg细胞的发育、表型和功能的研究很少; 2）如在大多数研究中分析的来自血液的Treg细胞可能不反映淋巴组织中的大多数Treg细胞; 3）Treg细胞在不同的HIV疾病阶段可能受到不同的影响;以及4）研究群体内和研究群体之间的年龄和遗传学的个体差异。迫切需要解决这些限制的强大动物模型来研究调节性T细胞在HIV感染中的作用。DKO-hu HSC模型非常适合此目的。我们可以产生具有个体人胎肝供体组织的DKO-hu小鼠的大的“近交系”群组（20-40只DKO-hu小鼠/供体FL组织）。由于具有稳定的功能性人免疫系统，功能性FoxP 3 + CD 4 + Treg细胞在DKO-hu小鼠的所有淋巴器官中以正常比例发育。HIV-1建立持续感染，具有特异性免疫应答、免疫超活化和人CD 4 T细胞耗竭。我推测Treg细胞在急性HIV感染期间在淋巴器官中被募集或诱导以调节免疫应答。这些CD 4 + Treg细胞也是支持高水平HIV复制的良好HIV靶细胞。AIDS进展期间的慢性HIV感染或致病性HIV变体的出现可能会损害/耗尽功能性Treg细胞，导致超免疫激活和AIDS进展。本项目将研究FoxP 3 + 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小鼠体内淋巴组织中Treg细胞的发育、功能和维持，以及它们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FoxP 3 + 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增加或减少DKO-hu HSC小鼠中的Treg细胞来测试Treg细胞在感染早期和HIV疾病进展的慢性阶段中的作用。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发病机制的经验。最重要的是，新型DKO-hu小鼠提供了第一个直接研究人类Treg细胞在体内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FoxP 3 + Treg细胞相互作用的机制及其在HIV-1感染和AIDS发病机制中的作用，将有助于我们更好地了解HIV-1感染和发病机制。这些发现不仅有助于我们理解HIV感染和发病机制中的Treg生物学，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感染和发病机制的最基本问题。阐明HIV-1与FoxP 3 + Treg细胞相互作用的机制及其在HIV-1感染和AIDS发病机制中的作用，将有助于我们更好地了解HIV-1感染和发病机制。这些发现不仅有助于我们理解HIV感染和发病机制中的Treg生物学，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.