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===========================================

超过提供的空间。原代人细胞的HIV感染通常需要与原代受体CD4和趋化感受器受体CCR或CXCR4相互作用。 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进入M0。这些研究可能会导致新型抗逆转录病毒抗体的发育，我们将在五年内追求这些目标：特定目标1。共核能（R5）以及使用CXCR4或CCRS（RSX4）和能够在M0中复制的X4菌株的双重菌株事件。特定目的2。检验以下假设：HIV靶细胞之间的细胞特异性差异会影响CD63在促进HIV进入中的作用。我们将控制和测试各种受体/共感受器/CD63表达和激活标志物01对抗CD63抑制的敏感性。 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与CD63，（b）CD63与GP120，（c）CD63在CD4周转或病毒/受体内吞作用和（d）信号转导的作用。这些实验将基于MLV-ENV伪型病毒（和X4 HIV-1菌株）的抗CD63敏感性进行优先级，如果抑制不依赖于CD4和CCRS相关事件，该实验将指导我们专注于后期事件。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疗法提供重要的新目标。表演场（===========================================================================================================

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.