Molecular and Cellular mechanisms of dendritic cell mediated HIV transmission

树突状细胞介导的HIV传播的分子和细胞机制

• 批准号: 7337037
• 负责人: DAVID J MCDONALD
• 金额: $ 23.18万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-20 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7337037
• 关键词: Acquired Immunodeficiency Syndrome; Adaptor Protein Complex 3; Adaptor Protein Complex Subunits; Antigen Presentation; Antigens; Area; Back; Bacteria; Binding; Blood; CD4 Antigens; CD4 Positive T Lymphocytes; Cell surface; Cells; Chromosome Pairing; Coculture Techniques; Condition; Dendritic Cells; Dominant-Negative Mutation; Event; Face; Family; Goals; Green Fluorescent Proteins; HIV; HIV Infections; HIV Receptors; Human; Image; Immune; Immune response; Immune system; Individual; Infection; Kinetics; Knowledge; Laboratories; Life; Mediating; Mediator of activation protein; Messenger RNA; Microscopy; Molecular; Movement; Multivesicular Body; Prevention; Prevention strategy; Process; Quantitative Microscopy; Recruitment Activity; Reporting; Resistance; Resolution; Role; Route; Signal Transduction; Site; Sorting - Cell Movement; Specificity; Structure; Surface; Synapses; System; Systemic infection; T-Lymphocyte; Testing; Time; Tissues; Ursidae Family; Variant; Vesicle; Viral; Virion; Virus; Work; cell type; chemokine; immunological synapse; inhibitor/antagonist; monocyte; particle; pathogen; prevent; receptor; research study; small hairpin RNA; trafficking; transmission process; uptake

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 dendritic cells 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. DCs can efficiently bind and transfer HIV infection without themselves becoming infected and can in fact greatly enhance the infection of target cells. DCs are therefore potentially important both in primary infection and in the persistence of viral reservoirs in infected individuals, making them an attractive target for new therapies aimed at prevention and treatment of HIV infection. My lab tracks the movement of HIV within and between living DCs and T-cells by tagging virions with the green fluorescent protein (GFP). We have previously reported that DCs effect enhancement of HIV infection by concentrating the virus to sites of intimate contact with CD4 T cells at the same time that the HIV receptors (CD4 and CXCR4/CCR5) are concentrated on the surface of the T cell. 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 formation the infectious synapse in living cells and examine the molecular events responsible for its formation. In addition, the molecular machinery responsible for HIV trafficking within DCs and delivery to target T cells will be evaluated by specific inhibition of individual effectors. Understanding the mechanisms of cell-to-cell transmission of HIV is crucial to understanding how the virus persists in the face of the human immune response. Undermining the very cells that should protect the body from infection is yet another example of how a relatively simple virus can outsmart the human immune system. The knowledge gained from this study will be useful in devising new strategies for the prevention and treatment of HIV infections. 7. Project Narrative Dendritic cells (DCs) are essential players in immune defense that patrol the gut and other tissues, picking up bacteria and viruses and destroying them in order to help T cells recognize the foreign invaders. When a dendritic cell picks up HIV, however, some of the virus survives inside the DC and is efficiently passed on to the T cell, causing the infections that eventually leads to AIDS. This project aims to identify the way that HIV avoids degradation and is passed into the T cell by direct observation of HIV particles in living cells using high resolution microscopy. We will identify the key players in the routing of the virus inside the DCs with the goal of devising new treatment strategies to prevent DC mediated infections.

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。血液树突状细胞巡逻身体易受病原体和吞噬抗原侵袭的人体巡逻区域，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。 DC可以有效地结合和转移HIV感染而不会被感染，实际上可以大大增强靶细胞的感染。因此，DC在原发性感染和感染个体的病毒储存术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。我的实验室通过用绿色荧光蛋白（GFP）标记病毒体来跟踪HIV在生存DC和T细胞之间的运动。我们先前已经报道说，DCS通过将病毒浓缩到与CD4 T细胞的紧密接触部位的同时，同时将HIV受体（CD4和CXCR4/CCR5）集中在T细胞的表面上。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讨形成活细胞中传染性突触的动力学，并检查负责其形成的分子事件。此外，将通过特定抑制单个效应子来评估负责DC内HIV运输并递送到目标T细胞内的HIV运输和递送到目标T细胞的分子机制。了解HIV的细胞到细胞传播的机制对于了解人类免疫反应时病毒如何持续存在至关重要。破坏应保护人体免受感染的细胞是一个相对简单的病毒如何能够超越人类免疫系统的另一个例子。从这项研究中获得的知识将有助于制定预防和治疗艾滋病毒感染的新策略。 7。项目叙事树突状细胞（DC）是巡逻肠道和其他组织的免疫防御中的重要参与者，吸收细菌和病毒并破坏它们以帮助T细胞识别外国入侵者。然而，当树突状细胞接收HIV时，某些病毒在DC内生存，并有效地传递到T细胞中，从而导致最终导致艾滋病的感染。该项目旨在确定HIV避免降解的方式，并通过使用高分辨率显微镜直接观察活细胞中的HIV颗粒传递到T细胞中。我们将确定DC内病毒路线的主要参与者，目的是制定新的治疗策略以防止DC介导的感染。