Virological Synapse and Signaling for Efficient HIV Transmission

HIV 有效传播的病毒突触和信号传导

• 批准号: 8391653
• 负责人: Catarina E Hioe
• 金额: --
• 依托单位: VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-10-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391653
• 关键词: 1,2-diacylglycerol; AIDS/HIV problem; Actins; Address; Affect; American; Anti-HIV Agents; Anti-Retroviral Agents; Antigenic Variation; Area; Binding; CD3 Antigens; CD4 Positive T Lymphocytes; CXCR4 gene; Caring; Cell Adhesion; Cell Adhesion Molecules; Cell Communication; Cell Membrane Proteins; Cell membrane; Cells; Cellular Membrane; Cellular Morphology; Chemokine (C-C Motif) Receptor 5; Cleaved cell; Collaborations; Cytoskeleton; DNA Sequence Rearrangement; Data; Development; Diglycerides; Event; Gagging; Genetic; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV-1; Healthcare; Herpesviridae; Human T-lymphotropic virus 1; Infection; Institutes; Integrins; Intercellular Junctions; LCP2 gene; Lead; Ligands; Link; Mediating; Membrane; Membrane Proteins; Microtubule-Organizing Center; Microtubules; Mission; Modality; Molecular; Pathway interactions; Patient Care; Patients; Pattern; Peptide/MHC Complex; Pharmaceutical Preparations; Phosphorylation; Physiological; Play; Process; Provider; Quality of life; Receptor Activation; Receptor Signaling; Recruitment Activity; Resistance; Role; Route; Side; Signal Pathway; Signal Transduction; Signal Transduction Inhibitor; Signal Transduction Pathway; Signaling Molecule; Staging; Survival Rate; Synapses; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Vaccines; Vesicle; Virion; Virus; Virus Assembly; ZAP-70 Gene; actin depolymerizing factor; cell motility; cell type; chemokine; cofilin; drug resistant virus; immunological synapse; inhibitor/antagonist; interest; neutralizing antibody; novel; polymerization; receptor; spatiotemporal; synaptogenesis; transmission process; virological synapse

DESCRIPTION (provided by applicant): Summary HIV, like many other viruses (e.g. HTLV-1 and herpes viruses), disseminates from infected cells to new target cells much more efficiently by cell-to-cell transmission as compared to cell-free virion transmission. Cell- to-cell transmission occurs in an infectious or virological synapse (VS), where a tight cleft between an infected cell and a target cell is formed as a result of firmly adhering plasma membranes of the two apposing cells. VS formation is initiated upon HIV envelope gp120 interaction with CD4 which then recruits specific cell membrane proteins including the relevant co-receptor (CCR5 or CXCR4) and cellular adhesion molecules. Importantly, VS also requires active participation of intracellular signaling molecules in both the gp120-expressing donor cell and the CD4+ target cell. Our recent studies demonstrate that in the target T cell ("efferent") side, a cascade of signaling events are triggered, starting from activation of CD4-associated Lck, to cause alteration of T cell motility and reorganization of actin cytoskeleton, each of which is potentially important for successful progression of the early stages of HIV transfer and infection at the VS. In the infected donor cell ("afferent") side, virus assembly and budding are also facilitated by Lck, which binds and directs HIV gag to the plasma membrane in the infected T cell. The importance of signaling molecules in VS formation presents an opportunity to exploit these signal transduction pathways for blocking HIV transmission and infection. In this application we will focus on HIV transmission from infected CD4 T cells to target CD4 T cells, the most common cell type infected by HIV, and define the membrane-proximal signaling molecules and pathways activated in the infected donor and uninfected target cells that are required for VS formation. Identifying these molecules and pathways will allow us the opportunity to inhibit their activity to stop HIV transmission through the VS. To achieve this, we will evaluate the importance of Lck activation and its downstream signaling events for efficient VS formation and cell-cell transmission of HIV (Aim 1). We will determine membrane-proximal signaling molecules that are recruited to VS in the infected donor cells and compare them with those found in the target T cells (Aim 2). The involvement of Lck and other activation signals in cytoskeleton reorganization that facilitates VS-mediated virus egress and entry will also be studied (Aim 3). Finally, we will determine how HIV Env interaction with the 1427 integrin on the target CD4 T cells affects HIV transmission via the VS, and VS formation and signaling (Aim 4). Identification of signaling molecules and pathways essential for VS formation should pave the way for the development of signal transduction inhibitors as a novel class of HIV inhibitors. There is a growing interest for such anti-HIV modalities as they circumvent the unprecedented problem of HIV-1 genetic and antigenic variability, which has hampered the development of efficacious HIV/AIDS vaccines and has led to the emergence of drug-resistant viruses.

描述（由申请人提供）： 与许多其他病毒（如HTLV-1和疱疹病毒）一样，HIV通过细胞间传播从感染细胞传播到新的靶细胞比无细胞病毒体传播更有效。细胞间传递发生在感染性或病毒学突触（VS）中，其中由于两个并列细胞的质膜牢固粘附，在感染细胞和靶细胞之间形成紧密的裂缝。VS的形成是在HIV包膜gp 120与CD 4相互作用后开始的，然后CD 4募集特异性细胞膜蛋白，包括相关的辅助受体（CCR 5或CXCR 4）和细胞粘附分子。重要的是，VS还需要表达gp 120的供体细胞和CD 4+靶细胞中的细胞内信号分子的积极参与。我们最近的研究表明，在靶T细胞中（“传出”）侧，从CD 4相关Lck的激活开始触发信号传导事件的级联，以引起T细胞运动性的改变和肌动蛋白细胞骨架的重组，其中每一个对于在VS处HIV转移和感染的早期阶段的成功进展都是潜在重要的。在受感染的T细胞（“传入”）侧，Lck也促进病毒组装和出芽，Lck结合HIV gag并将其引导至受感染的T细胞中的质膜。信号分子在VS形成中的重要性为利用这些信号转导途径阻断HIV传播和感染提供了机会。在本申请中，我们将重点关注HIV从感染的CD 4 T细胞向靶CD 4 T细胞（HIV感染的最常见细胞类型）的传播，并定义在感染供体和未感染靶细胞中激活的近膜信号分子和途径，这些分子和途径是VS形成所需的。鉴定这些分子和途径将使我们有机会抑制其活性，以阻止HIV通过VS传播。为了实现这一目标，我们将评估Lck激活及其下游信号传导事件对有效的VS形成和HIV的细胞-细胞传播的重要性（目的1）。我们将确定在受感染的供体细胞中招募到VS的近膜信号分子，并将其与靶T细胞中发现的分子进行比较（目的2）。还将研究Lck和其他活化信号参与促进VS介导的病毒外出和进入的细胞骨架重组（Aim 3）。最后，我们将确定HIV Env与靶CD 4 T细胞上的1427整联蛋白的相互作用如何通过VS影响HIV传播，以及VS形成和信号传导（目的4）。VS形成所必需的信号分子和途径的鉴定应该为信号转导抑制剂作为一类新的HIV抑制剂的发展铺平道路。人们对这种抗艾滋病毒方法越来越感兴趣，因为它们避免了前所未有的HIV-1遗传和抗原变异性问题，这一问题阻碍了有效的HIV/艾滋病疫苗的开发，并导致抗药性病毒的出现。