HIV-1 Replication and Pathogenesis in vivo

HIV-1体内复制和发病机制

• 批准号: 8288315
• 负责人: Lishan Su
• 金额: $ 36.63万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-22 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8288315
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Affinity; Binding; Biology; CCR5 gene; CD4 Antigens; CD4 Positive T Lymphocytes; CXCR4 gene; Cells; Chronic; Defect; Development; Disease Progression; Endosomes; Genes; Genetic; Goals; HIV; HIV Infections; HIV-1; Homeostasis; Human; Immune; Immune system; Impairment; In Vitro; Infection; Ligands; Lymphoid; Lymphoid Tissue; Modeling; Molecular; Monkeys; Mus; Organ; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Play; Regulation; Relative (related person); Reporting; Role; SIV; Signal Pathway; Signal Transduction; Signaling Pathway Gene; TLR7 gene; Testing; Toxin; Virus Diseases; base; immune activation; in vivo; in vivo Model; inhibitor/antagonist; migration; novel; novel therapeutics; receptor; sensor; small hairpin RNA

forARRA years 1-2funding The goals of this project are to define how HIV-1 interacts with pDC and to elucidate the role of pDC cells in HIV-1 replication and pathogenesis. As the major sensor of viral infections, altered pDC level/activity may playa critical role during HIV-1 disease progression. However, the role of pDC cells in F-IIV infection and pathogenesis is poorly understood, mainly due to the lack of robust in vivo models. The DKO-hu I-4SC model is ideal for this purpose. With a stable functional human immune system, functional pDC cells are developed in normal proportion in all lymphoid organs in DKO-hu mice. HIV-1 establishes persistent infection, with immune hyperactivation and depletion of human CD4 T cells. We have also shown that, during HIV-1 infection, PDC cells are productively infected, activated, depleted and functionally impaired in DKO-hu HSC mice. HIV-1 with the pathogenic R3A Env also efficiently activates PDC in vitro, correlated with its high binding affinity to CD4 receptor and coreceptors. Based on our preliminary findings and reports from Sly-infected monkeys or HIV- infected patients, postulate that HIV-1 intimately interacts with PDC cells, and chronic engaging of PDC during persistent HIV infection wifl deplete or impair PDC activity. The reduced or altered PDC activity contributes to chronic HIV infection, hyperimmune activation and AIDS progression. The following modified specific aims are proposed to test these hypotheses. First, we wil iinvestigate the Induced by HIV infection, by genetically analyzing the candidate signaling pathways (SA2a). Third, we will proliferation and survival of pOC cells during early and late-chronic HIV-1 pDC activation with genetic approaches. In addition, we will also define the signaling defects in pOC cells Second, we will define the role of each relevant receptor (CD4, CCR5, CXCR4, BDCA2, TLR7 and TLR9) in pDC activation with specific inhibitors and with genetic approaches. In addition, we will also purify pDC cells from mock- or HIV-infected DKO-hu mice to identify genes that are deregulated by HIV infection. We will define the signaling defects in pDC cells induced by HIV infection, by genetically analyzing the candidate signaling pathways. Third, we will study if stimulation or inhibition of pDC activation with the agonistic or antagonistic ligands of TLR7/TLR9 before or during HIV infection will affect HIV replication and immuno-pathogenesis. In addition, we will treat DKO-hu mice with the pDC-specific mAb conjugated with the Saporin toxin, which specifically depletes pDC, to test the role of pDC during infection. We will thus focus on the most fundamental questions of pDC cells in HIV pathogenesis. Elucidation of the mechanism by which HIV-1 interacts with pDC cells and their role in HIV-1 infection and AIDS pathogenesis will facilitate not only our understanding of pDC biology in HIV pathogenesis, but also development of novel therapeutic strategies.

为 ARRA 第 1-2 年提供资金 该项目的目标是定义 HIV-1 如何与 pDC 相互作用并阐明 pDC 的作用 HIV-1 复制和发病机制中的细胞。作为病毒感染的主要传感器，pDC 水平/活性发生改变 可能在 HIV-1 疾病进展过程中发挥关键作用。然而，pDC 细胞在 F-IIV 感染和 发病机制尚不清楚，主要是由于缺乏可靠的体内模型。 DKO-hu I-4SC 型号是 非常适合此目的。凭借稳定的功能性人类免疫系统，功能性 pDC 细胞在 DKO-hu 小鼠所有淋巴器官中的正常比例。 HIV-1 建立持续感染，并具有免疫功能 人类 CD4 T 细胞的过度激活和耗竭。我们还表明，在 HIV-1 感染期间，PDC DKO-hu HSC 小鼠中的细胞被有效感染、激活、耗尽和功能受损。 HIV-1 与 致病性 R3A Env 还可在体外有效激活 PDC，这与其与 CD4 的高结合亲和力相关 受体和辅助受体。根据我们对感染 Sly 的猴子或 HIV 的初步调查结果和报告 感染患者，假设 HIV-1 与 PDC 细胞密切相互作用，并且 PDC 长期参与 在持续的 HIV 感染期间，PDC 活性将被耗尽或损害。 PDC活性降低或改变 导致慢性艾滋病毒感染、过度免疫激活和艾滋病进展。 提出以下修改后的具体目标来检验这些假设。首先，我们将调查 通过对候选信号通路 (SA2a) 进行基因分析，由 HIV 感染诱导。第三，我们将 早期和晚期 HIV-1 期间 pOC 细胞的增殖和存活 通过遗传方法激活 pDC。此外，我们还将定义pOC细胞中的信号传导缺陷 其次，我们要定义角色 pDC 激活中每个相关受体（CD4、CCR5、CXCR4、BDCA2、TLR7 和 TLR9）的变化 特异性抑制剂和遗传方法。此外，我们还将从模拟或实验中纯化 pDC 细胞。 HIV 感染的 DKO-hu 小鼠可识别因 HIV 感染而失调的基因。我们将定义 通过对候选信号进行基因分析，发现 HIV 感染引起的 pDC 细胞中的信号缺陷 途径。第三，我们将研究激动剂或激动剂是否刺激或抑制 pDC 活化。 HIV感染前或感染期间TLR7/TLR9的拮抗配体会影响HIV复制和 免疫发病机制。此外，我们将使用缀合的 pDC 特异性 mAb 治疗 DKO-hu 小鼠 与皂素毒素（其专门消耗 pDC）一起测试 pDC 在感染过程中的作用。 因此，我们将重点关注 pDC 细胞在 HIV 发病机制中最基本的问题。阐明 HIV-1 与 pDC 细胞相互作用的机制及其在 HIV-1 感染和艾滋病中的作用 发病机制不仅将促进我们对 HIV 发病机制中 pDC 生物学的理解，而且 开发新的治疗策略。

项目成果

HIV-1 Env and Nef Cooperatively Contribute to Plasmacytoid Dendritic Cell Activation via CD4-Dependent Mechanisms.

HIV-1 Env 和 Nef 通过 CD4 依赖性机制协同促进浆细胞样树突状细胞激活。

• 发表时间: 2015-08
• 作者: Reszka;Sivaraman, Vijay;Zhang, Liguo;Su, Lishan
• 通讯作者: Su, Lishan

SCARB2/LIMP-2 Regulates IFN Production of Plasmacytoid Dendritic Cells by Mediating Endosomal Translocation of TLR9 and Nuclear Translocation of IRF7.

SCARB2/LIMP-2 通过介导 TLR9 的内体转位和 IRF7 的核转位来调节浆细胞样树突状细胞的 IFN 产生。

• 发表时间: 2015-05-15
• 作者: Guo, Hao;Zhang, Jialong;Zhang, Xuyuan;Wang, Yanbing;Yu, Haisheng;Yin, Xiangyun;Li, Jingyun;Du, Peishuang;Plumas, Joel;Chaperot, Laurence;Chen, Jianzhu;Su, Lishan;Liu, Yongjun;Zhang, Liguo
• 通讯作者: Zhang, Liguo

Ribavirin Contributes to Hepatitis C Virus Suppression by Augmenting pDC Activation and Type 1 IFN Production.

利巴韦林通过增强 pDC 激活和 1 型干扰素产生来抑制丙型肝炎病毒。

• 发表时间: 2015
• 影响因子: 3.7
• 作者: Wang, Yang;McGivern, David R;Cheng, Liang;Li, Guangming;Lemon, Stanley M;Niu, Junqi;Su, Lishan;Reszka
• 通讯作者: Reszka

Glycosylphosphatidylinositol-Anchored Anti-HIV scFv Efficiently Protects CD4 T Cells from HIV-1 Infection and Deletion in hu-PBL Mice.

糖基磷脂酰肌醇锚定的抗 HIV scFv 有效保护 hu-PBL 小鼠中 CD4 T 细胞免受 HIV-1 感染和缺失。

• 发表时间: 2017-02-01
• 作者: Ye, Chaobaihui;Wang, Weiming;Cheng, Liang;Li, Guangming;Wen, Michael;Wang, Qi;Zhang, Qing;Li, Dan;Zhou, Paul;Su, Lishan
• 通讯作者: Su, Lishan

Blocking type I interferon signaling enhances T cell recovery and reduces HIV-1 reservoirs.

阻断 I 型干扰素信号传导可增强 T 细胞恢复并减少 HIV-1 储存库。

• 发表时间: 2017-01-03
• 作者: Cheng, Liang;Ma, Jianping;Li, Jingyun;Li, Dan;Li, Guangming;Li, Feng;Zhang, Qing;Yu, Haisheng;Yasui, Fumihiko;Ye, Chaobaihui;Tsao, Li;Hu, Zhiyuan;Su, Lishan;Zhang, Liguo
• 通讯作者: Zhang, Liguo