Dendritic cell enhancement of HIV infection

树突状细胞增强HIV感染

• 批准号: 6746772
• 负责人: DAVID J MCDONALD
• 金额: $ 23.25万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-29 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6746772
• 关键词: HIV infections; T cell receptor; T lymphocyte; biological signal transduction; cell cell interaction; cell migration; clinical research; dendritic cells; human immunodeficiency virus; human subject; intracellular transport; surface antigens; virus infection mechanism

DESCRIPTION (provided by applicant): Dendritic cells (DCs) comprise a multivariate family of cell types whose principal function is in the primary initiation of immune responses. Blood or myeloid-derived dendritic cells (MDDCs) patrol areas of the body that are susceptible to invasion by pathogens and engulf antigens for later processing and presentation to T lymphocytes. HIV has apparently appropriated this feature of the immune system to better establish and maintain infection of its primary target--CD4 positive T cells. MDDCs can efficiently bind and transfer HIV infectivity without themselves becoming infected. Under conditions of limiting soluble virus, MDDCs greatly enhance infection of target cells. DCs are therefore potentially important both in primary infection and in the persistence of drug-resistant reservoirs in infected individuals, making them an attractive target for new therapies aimed at prevention and treatment of HIV infection. We have begun to examine the trafficking of HIV between DCs and T cells using our unique system of directly visualizing HIV in cells by tagging virions with the green fluorescent protein. Live cell video microscopy revealed that HIV is recruited to sites of cell contact in MDDCs, even when surface HIV is removed by proteolysis. Analysis of conjugates between MDDCs and autologous T cells showed that, even in the absence of antigen-specific signaling, the HIV receptors CD4 and CXCR4 on the T cell are recruited to the interface and a significant proportion of MDDCs concentrate HIV to the same region. Because this structure bears similarities to the antigen signaling structure known as the immunological synapse, we refer to it as the infectious synapse. The experiments proposed here will explore the dynamics of the formation the infectious synapse and examine the signaling events responsible for its formation. Additionally, the efficacy of a new class of HIV anti-viral compounds that target HIV fusion and entry will be assessed, providing important information about potential resistance to this therapeutic approach. Finally, the mechanism of transmission will be investigated, focusing on whether HIV is displayed on the DC surface prior to infection of the target, or if it is secreted from the cell in the form of exosomes. Elucidation of this mechanism will be important for the design of new anti-viral compounds that might ultimately lead to the eradication of this drug-resistant pool of infectious HIV.

描述（由申请人提供）：树突状细胞（DC）构成了一个多元类型的多元家族，其主要功能是免疫反应的主要启动。血液或髓样衍生的树突状细胞（MDDC）巡逻区域，这些巡逻区容易受到病原体和吞噬抗原的侵袭，以便以后的加工和表现为T淋巴细胞。 HIV显然已经使用了免疫系统的这一特征，以更好地建立和维持其主要靶标-CD4阳性T细胞的感染。 MDDC可以有效地结合和转移HIV感染性，而不会自身被感染。在限制可溶性病毒的条件下，MDDC大大增强了靶细胞的感染。因此，DC在原发性感染和受感染个体中抗药性储层的持续性中可能非常重要，这使其成为旨在预防和治疗HIV感染的新疗法的有吸引力的靶标。我们已经开始使用我们的独特的DCS和T细胞之间的艾滋病毒在细胞中直接可视化细胞中的艾滋病毒的系统来检查细胞中的艾滋病毒，该系统通过用绿色荧光蛋白标记病毒体。实时细胞视频显微镜表明，即使通过蛋白水解去除表面HIV，HIV也被募集到MDDC中的细胞接触部位。对MDDC和自体T细胞之间的共轭物的分析表明，即使没有抗原特异性信号传导，T细胞上的HIV受体CD4和CXCR4也会募集到界面上，并且MDDC浓度很大，MDDC浓度为HIV到同一区域。因为该结构与称为免疫突触的抗原信号结构相似，所以我们称其为传染性突触。这里提出的实验将探索形成的动力学传染性突触，并检查负责其形成的信号传导事件。此外，将评估针对HIV融合和进入的新型HIV抗病毒化合物的功效，从而提供有关这种治疗方法的潜在抗性的重要信息。最后，将研究传播的机理，重点是在靶标感染之前在直流表面显示HIV，还是以外泌体形式从细胞中分泌。阐明这种机制对于设计新的抗病毒化合物的设计至关重要，这最终可能导致消除这种耐药性感染性HIV池。