SIGNALLING FUNCTION OF CD4 AND ITS ROLE IN MODIFYING T-CELL ACTIVATION

探讨HIV-CD 4的生物学和免疫学后果 相互作用，我们已经开始研究分析功能变化， 其继发于病毒、病毒包膜或 正常T细胞表面的CD 4抗体。 初步研究 目的是评价多种抗CD 4和其他细胞因子的单克隆抗体， 表面分子，沿着包膜蛋白和纯化的HIV， 确定这些试剂是否共刺激或抑制T细胞 受体启动的T细胞活化。 我们发现， 如单克隆抗体所定义的，CD 4分子上的表位是 能够向T细胞传递不同的信号。 有些网站非常 当存在于溶液中时，有效抑制T细胞活化，其中 因为其他人唤起强烈的刺激活动的背景下， 来自T细胞受体的交联同步信号。 这些 功能差异可能代表类型或质量的差异 对CD 4分子上不同表位的反应产生的信号。 当在同一系统中分析艾滋病毒的影响时， 类似于抗CD 4单克隆抗体的那些是显而易见的。 然而，在这方面， 病毒和包膜的功能作用范围更广， 除了可以分配给对 CD 4分子。 这些刺激和抑制活性可能取决于 在病毒CD 4结合区之外的包膜位点，或者甚至是 继发于存在于病毒表面的其他蛋白质。 我们也 目前正在研究产生的生化信号。由不同 CD 4抗体。 最近的观察表明，CD 4 可以增强细胞内钙浓度的增加， 继发于蛋白激酶活化。 我们的目标是定义和 了解CD 4和CD 4+细胞之间的分子和生物化学差异 产生消极和积极的信号。 这些途径大概 是HIV改变宿主T细胞功能的途径。

To investigate the biological and immunological consequences of HIV-CD4 interactions, we have initiated studies to analyze the functional changes which occur secondary to the binding of either virus, virus envelope, or antibodies to CD4 on the surface of normal T-cells. The initial studies are to evaluate a variety of monoclonal antibodies to CD4 and other cell surface molecules, along with envelope proteins and purified HIV to determine whether these reagents either co-stimulate or inhibit T-cell receptor initiated T-cell activation. We have found that different epitopes on the CD4 molecule, as defined by monoclonal antibodies, are able to transmit different signals to the T-cell. Some sites are very potent at inhibiting T-cell activation when presented in solution, where as others evoke strong stimulatory -activity in the context of a crosslinked simultaneous signal from the T-cell receptor. These functional differences may represent differences in the type or quality of signal generated in response to distinct epitopes on the CD4 molecule. When the effects of HIV are analyzed in the same systems, activities similar to those of monoclonal antibodies to CD4 are apparent. However, the functional effects of virus and envelope are much broader and extend beyond interactions that can be assigned to an exclusive effect on the CD4 molecule. These stimulatory and inhibitory activities may depend on envelope sites outside of the virus CD4 binding region or even be secondary to other proteins present on the viral surface. We are also currently studying the biochemical signaling generated. by different antibodies to CD4. Recent observations suggest that crosslinking of CD4 can potentiate increases in intracellular calcium concentrations possibly secondary to protein kinase activation. Our goal is to define and understand the molecular and biochemical differences between CD4 generated negative and positive signalling. These pathways presumably are routes by which HIV can modify the function of the host T-cell.