Role of Tetraspan Glycoproteins (CD63) in HIV Entry

四跨糖蛋白 (CD63) 在 HIV 进入中的作用

• 批准号: 6833509
• 负责人: WILLIAM AUSTIN O'BRIEN
• 金额: $ 33.53万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-15 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6833509
• 关键词: Role; Tetraspan; Glycoproteins; CD63; HIV

EXCEEDTHE SPACE PROVIDED. HIV infection of primary human cells typically requires interaction with both the primary receptor CD4 and a chemokinecoreceptor either CCRS or CXCR4. We have discovered a potential role for CD63 in HIV infection of M0, as monoclonal antibodies (mAb specific for CD63 can prevent HIV entry into MO, but not T-cells. CD63 is a tetraspan membrane glycoprotein, best known as a1 activation marker on platelets, that is nearly ubiquitous on human cells and is closely associated with integrins. Our experimentswil investigate the role of CD63 in HIV entry into M0. These studies may lead to developmentof novel antiretroviraltherapies targetini HIV entry. We will pursue these Aims over five years: Specific Aim 1. To test the hypothesis that infection of M0by diverse primary HIV-1 strains can be inhibited by anti-CD63 mAb This will include both subtype B and non-subtypeB strains, includingsome that use CCRS as a coreceptor (R5), as well as dual-tropic strains that use either CXCR4 or CCRS (RSX4), and X4 strains able to replicate in M0. Amphotropic MLV-Env-pseudotyped virus which enters independent of CD4 and CCRYCXCR4 interactions, will be assessed to determine if anti-CD63 irhbition acts at post binding retroviral entry events. Specific Aim 2. To test the hypothesis that cell-specific differences between HIV target cells affect the role of CD63 in facilitatini HIV entry. We will control for and test effects of various levels of receptor/coreceptor/CD63 expression and activation markers 01 susceptibility to anti-CD63 inhibition. We will also test cell line models of anti-CD63 inhibition, which would facilitate cel manipulation and the consistencycif lnhibitoryeffects in these studies,and in the mechanistic studiesin Aim 3. Specific Aim 3. To test the hypothesis that CD63 has a specific role in facilitating HIV entry into macrophages, we will identify potential mechanisms of CD63-mediatedHIV entry, including (a) receptor/coreceptor interactions or colocalization with CD63, (b) CD63 binding to gp120, (c) the role of CD63 in CD4 turnover or virus/receptor endocytosis and (d) signal transduction. These experiments will be prioritized based on anti-CD63 susceptibility of MLV-Env pseudotyped virus (and X4 HIV-1 strains), which would direct us to focus on late events if inhibition is not dependent on CD4 and CCRS-associated events. Achieving these Aims will provide important new insights into the mechanism of HIV-1 entry, and may well provide important new targets for antiretroviraltherapy. PERFORMANCESITE( ========================================Section End===========================================

超出提供的空间。原代人类细胞的 HIV 感染通常需要与原代受体 CD4 和趋化因子辅助受体 CCRS 或 CXCR4 相互作用。我们发现 CD63 在 M0 的 HIV 感染中具有潜在作用，作为单克隆抗体（CD63 特异性的 mAb 可以阻止 HIV 进入 MO，但不能阻止 T 细胞。CD63 是一种四跨膜糖蛋白，最广为人知的是血小板上的 a1 激活标记，它在人类细胞中几乎无处不在，并且与整合素密切相关。我们的实验将研究 CD63 在 HIV 进入 M0 中的作用。这些研究可能会导致新的研究的发展。我们将在五年内追求这些目标： 具体目标 1. 检验抗 CD63 mAb 可以抑制不同原发性 HIV-1 毒株对 M0 的感染的假设 这将包括 B 亚型和非 B 亚型。菌株，包括一些使用 CCRS 作为辅助受体 (R5) 的菌株，以及使用 CXCR4 或 CCRS (RSX4) 和 X4 的双向菌株将评估能够在 M0 中复制的兼嗜性 MLV-Env 假型病毒，该病毒不依赖于 CD4 和 CCRYCXCR4 相互作用而进入，以确定抗 CD63 抑制是否在结合后逆转录病毒进入事件中起作用。具体目标 2. 检验 HIV 靶细胞之间的细胞特异性差异影响 CD63 在促进 HIV 进入中的作用的假设。我们将控制并测试不同水平的受体/辅助受体/CD63表达和激活标记01对抗CD63抑制的敏感性的影响。我们还将测试抗 CD63 抑制的细胞系模型，这将有助于细胞操作和这些研究以及目标 3 中的机制研究中的一致性 cif 抑制效应。 具体目标 3. 测试 CD63 在促进HIV 进入巨噬细胞，我们将确定 CD63 介导的 HIV 进入的潜在机制，包括 (a) 受体/辅助受体相互作用或与 CD63 共定位，(b) CD63与 gp120 的结合，(c) CD63 在 CD4 周转或病毒/受体内吞作用中的作用，以及 (d) 信号转导。这些实验将根据 MLV-Env 假型病毒（和 X4 HIV-1 毒株）的抗 CD63 敏感性进行优先排序，如果抑制不依赖于 CD4 和 CCRS 相关事件，这将指导我们关注晚期事件。实现这些目标将为 HIV-1 进入机制提供重要的新见解，并很可能为抗逆转录病毒治疗提供重要的新目标。表演网站（==========================================部分结束====== =======================================

项目成果

A critical role for CD63 in HIV replication and infection of macrophages and cell lines.

• DOI: 10.1016/j.virol.2008.06.029
• 发表时间: 2008-09-30
• 期刊: VIROLOGY
• 影响因子: 3.7
• 作者: Chen, Hui;Dziuba, Natallia;Friedrich, Brian;von Lindern, Jana;Murray, James L.;Rojo, Daniel R.;Hodge, Thomas W.;O'Brien, William A.;Ferguson, Monique R.
• 通讯作者: Ferguson, Monique R.