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：
8391653
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/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

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）：摘要 HIV 与许多其他病毒（例如 HTLV-1 和疱疹病毒）一样，通过细胞间传播比无细胞病毒颗粒传播更有效地从受感染细胞传播到新的靶细胞。细胞间传播发生在感染性或病毒性突触（VS）中，其中受感染细胞和靶细胞之间由于两个相邻细胞的质膜牢固粘附而形成紧密的间隙。 VS 形成是在 HIV 包膜 gp120 与 CD4 相互作用时启动的，然后招募特定的细胞膜蛋白，包括相关的辅助受体（CCR5 或 CXCR4）和细胞粘附分子。重要的是，VS 还需要表达 gp120 的供体细胞和 CD4+ 靶细胞中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（“传出”）侧，从 CD4 相关 Lck 的激活开始，触发一系列信号事件，导致 T 细胞运动性的改变和肌动蛋白细胞骨架的重组，其中每个事件对于艾滋病病毒传播和 VS 感染早期阶段的成功进展具有潜在的重要意义。在受感染的供体细胞（“传入”）侧，Lck 也促进病毒组装和出芽，Lck 将 HIV gag 结合并引导到受感染 T 细胞的质膜上。信号分子在 VS 形成中的重要性为利用这些信号转导途径来阻止 HIV 传播和感染提供了机会。在此应用中，我们将重点关注 HIV 从受感染的 CD4 T 细胞到目标 CD4 T 细胞（最常见的 HIV 感染细胞类型）的传播，并定义在受感染的供体和未受感染的靶细胞中激活的近膜信号分子和通路， VS 形成所需的。识别这些分子和途径将使我们有机会抑制它们的活性，从而阻止 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于有效 VS 形成和 HIV 细胞间传播的重要性（目标 1）。我们将确定受感染供体细胞中 VS 募集的近膜信号分子，并将它们与目标 T 细胞中发现的分子进行比较（目标 2）。还将研究 Lck 和其他激活信号在促进 VS 介导的病毒出入的细胞骨架重组中的参与（目标 3）。最后，我们将确定 HIV Env 与目标 CD4 T 细胞上的 1427 整合素相互作用如何影响 HIV 通过 VS 的传播以及 VS 的形成和信号传导（目标 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型 HIV 抑制剂的开发铺平道路。人们对这种抗艾滋病毒模式越来越感兴趣，因为它们规避了前所未有的 HIV-1 遗传和抗原变异问题，这一问题阻碍了有效的艾滋病毒/艾滋病疫苗的开发，并导致了耐药病毒的出现。