Virological Synapse and Signaling for Efficient HIV Transmission

HIV 有效传播的病毒突触和信号传导

基本信息

批准号：
8240325
负责人：
Catarina E Hioe
金额：
--
依托单位：
VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/8240325
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

项目摘要

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（例如HTLV-1和疱疹病毒）一样，与无细胞向细胞传播相比，与许多其他病毒（例如HTLV-1和疱疹病毒）一样，HIV将其从感染细胞传播到新靶细胞。细胞单细胞的传播发生在传染性或病毒式突触（VS）中，其中被感染细胞和靶细胞之间的紧密裂缝是由于两个附属细胞的牢固粘附的质膜而形成的。 VS形成是在HIV包膜GP120与CD4相互作用的情况下启动的，CD4随后募集了特定的细胞膜蛋白，包括相关的共受体（CCR5或CXCR4）和细胞粘附分子。重要的是，V还需要在表达GP120的供体细胞和CD4+靶细胞中积极参与细胞内信号分子。我们最近的研究表明，在目标T细胞（“ Ferferent”）方面，从激活CD4相关的LCK开始引发一系列信号事件，以引起T细胞运动性的改变和肌动蛋白细胞骨架的重新组织，每种肌动蛋白骨骼的重组对于HIV转移和HIV转移和感染的早期阶段都可能很重要，这是潜在的在受感染的供体细胞（“传入”）侧，LCK还促进了病毒组装和萌芽，该病毒和萌芽促进了感染T细胞中的质膜的结合并将HIV GAG与质膜有关。 VS形成中信号分子的重要性为开发这些信号转导途径的机会提供了阻止HIV传播和感染的这些信号转导途径。在此应用中，我们将重点介绍从感染的CD4 T细胞到靶向CD4 T细胞的艾滋病毒传播，CD4 T细胞是受HIV感染的最常见细胞类型，并定义了在感染的供体和未感染的靶细胞中激活VS形成所需的感染供体和未感染的靶细胞中的膜 - 透明体信号分子和途径。识别这些分子和途径将使我们有机会抑制其活性以阻止VS的HIV传播。为了实现这一目标，我们将评估LCK激活及其下游信号事件对HIV的有效形成和细胞细胞传播的重要性（AIM 1）。我们将确定被感染供体细胞中VS募集到VS的膜 - 透明信号分子，并将其与目标T细胞中发现的细胞进行比较（AIM 2）。 LCK和其他激活信号的参与还将研究促进VS介导的病毒流出和进入的细胞骨架重组（AIM 3）。最后，我们将确定靶标CD4 T细胞上与1427整合素的HIV ENV相互作用如何通过VS影响HIV的传播以及VS形成和信号传导（AIM 4）。鉴定信号分子和对形成必不可少的途径的识别应该为发展信号转导抑制剂作为新的HIV抑制剂的发展铺平道路。这种抗HIV模式的兴趣越来越大，因为它们避免了HIV-1遗传和抗原变异性的前所未有的问题，这阻碍了有效的HIV/AIDS疫苗的发展，并导致了抗药性病毒的出现。