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.

Forarra年1 - 2筹 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复制和发病机理中的细胞。作为病毒感染的主要传感器，PDC水平/活性改变了 可能在HIV-1疾病进展中的Playa关键作用。但是，PDC细胞在F-IIV感染中的作用和 发病机理的理解很少，这主要是由于体内模型缺乏健壮的原因。 DKO-HU I-4SC模型是 为此目的的理想选择。使用稳定的功能性人体免疫系统，功能性PDC细胞在 DKO-HU小鼠的所有淋巴器官中的正常比例。 HIV-1建立持续感染，免疫 人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 细胞在DKO-HU HSC小鼠中有效地感染，激活，耗尽并在功能上受损。 HIV-1与 致病性R3A ENV还有效地在体外激活了PDC，与其与CD4的高结合亲和力相关 受体和受体。根据我们的初步发现和狡猾感染的猴子或HIV-的报告 感染患者，假设HIV-1与PDC细胞密切相互作用，PDC的慢性参与 在持续的HIV感染期间，WIFL耗竭或损害PDC活性。降低或改变的PDC活性 有助于慢性HIV感染，高免疫激活和有助于进展。 提出了以下修改的特定目的来检验这些假设。首先，我们将对 通过HIV感染诱导，通过基因分析候选信号通路（SA2A）诱导。第三，我们会的 早期和晚期HIV-1期间POC细胞的增殖和存活 PDC用遗传方法激活。此外，我们还将定义POC细胞中的信号缺陷 其次，我们将定义角色 PDC激活中每个相关受体（CD4，CCR5，CXCR4，BDCA2，TLR7和TLR9）的 特定的抑制剂和遗传方法。此外，我们还将从模拟或 HIV感染的DKO-HU小鼠以鉴定受HIV感染失控的基因。我们将定义 通过基因分析候选信号传导，通过HIV感染诱导的PDC细胞中的信号传导缺陷 途径。第三，我们将研究使用激动剂或抑制PDC激活的刺激或抑制 在HIV感染之前或期间，TLR7/TLR9的拮抗配体会影响HIV复制和 免疫致病发生。此外，我们将使用PDC特异性mAb共轭治疗DKO-HU小鼠 与特异性耗尽PDC的糖蛋白毒素一起测试PDC在感染过程中的作用。 因此，我们将关注HIV发病机理中PDC细胞最基本的问题。阐明 HIV-1与PDC细胞相互作用的机制及其在HIV-1感染中的作用和AIDS的作用 发病机理不仅会促进我们对HIV发病机理中PDC生物学的理解，还将促进 开发新颖的治疗策略。

项目成果

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

• DOI: 10.4049/jimmunol.1402312
• 发表时间: 2015-05-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Guo H;Zhang J;Zhang X;Wang Y;Yu H;Yin X;Li J;Du P;Plumas J;Chaperot L;Chen J;Su L;Liu Y;Zhang L
• 通讯作者: Zhang L

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。

• DOI: 10.1371/journal.pone.0135232
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Wang,Yang;McGivern,DavidR;Cheng,Liang;Li,Guangming;Lemon,StanleyM;Niu,Junqi;Su,Lishan;Reszka-Blanco,NataliaJ
• 通讯作者: Reszka-Blanco,NataliaJ

Plasmacytoid dendritic cells promote HIV-1-induced group 3 innate lymphoid cell depletion.

• DOI: 10.1172/jci82124
• 发表时间: 2015-09
• 期刊: The Journal of clinical investigation
• 作者: Zheng Zhang;L. Cheng;Juanjuan Zhao;Guangming Li;Liguo Zhang;Weiwei Chen;Weimin Nie;Natalia J. Reszka-Blanco;Fu-Sheng Wang;L. Su