Dianzani U, Bragardo M, Buonfiglio D, Redoglia V, Funaro A, Portoles P, Rojo J, Malavasi F, Pileri A
Dipartimento di Scienze Mediche, Università di Torino, Italy.
Eur J Immunol. 1995 May;25(5):1306-11. doi: 10.1002/eji.1830250526.
CD4, a lymphocyte surface glycoprotein, serves as co-receptor for antigen with the T cell receptor (TCR). It is also the lymphocyte receptor for HIV by binding the gp120 viral envelope protein. Interaction of gp120 with CD4 is crucial for viral infection, but is not sufficient to allow viral entry into cells. Recombinant gp120 alters CD4+ T cell responsiveness to activation stimuli. To express its co-receptor function fully, CD4 must be laterally associated with the TCR and CD45 to form multi-receptor complexes competent to transduce potent activation signals. Here, we examine the possibility that gp120/CD4 binding alters lateral associations of CD4 with other lymphocyte surface molecules, and that assembly of abnormal multi-molecular complexes is involved in the gp120-induced CD4+ T cell dysfunction and in viral entry. In the absence of gp120, CD4 displayed high association with CD3, CD5, CD45RC, CD25, CD28, CD44, and CD53; weak association with CD2, CD38, CD45RB, CD62L, and CD26; and no association with CD45RA, CD45RO, CD11b, CD11a, CD54, CD7, CD48, CD98, CD59 CD55, HLA class I and class II molecules. Treatment with gp120 significantly increased CD4 association with CD3, CD45RA, CD45RB, CD59, CD38, CD26 and HLA class I, and decreased that with CD45RC. Specificity of these results were assessed at various levels. First, gp120 did not influence lateral associations displayed by other molecules, such as HLA class II. Second, the Leu3 mAb which binds CD4 on a site overlapping the gp120 binding site, did not elicit the same CD4 lateral associations as gp120, and finally, a direct gp120/CD4+ interaction was needed to induce the lateral associations, as shown by the observation that blocking the gp120/CD4 binding by the Leu3 mAb inhibited the gp120-induced associations. These results can be interpreted in several ways gp120/CD4 interaction could trigger an inside-out signal responsible for the associations, or gp120 could induce steric modifications of CD4 that increase its affinity for the associating molecules. Alternatively, these molecules may interact directly with gp120, bridging them with CD4. It is also possible that th e associations may be mediated by additional components, interacting with both gp120 and the associating surface molecule. The last hypothesis is likely for CD59, whose gp120-induced association with CD4 required the presence of serum in the co-capping assay. Since both CD59 and gp120 bind complement, the observed association could be mediated by complement components.
CD4是一种淋巴细胞表面糖蛋白，作为与T细胞受体（TCR）共同识别抗原的受体。它也是HIV的淋巴细胞受体，通过结合gp120病毒包膜蛋白发挥作用。gp120与CD4的相互作用对病毒感染至关重要，但不足以使病毒进入细胞。重组gp120会改变CD4 + T细胞对激活刺激的反应性。为了充分发挥其共受体功能，CD4必须与TCR和CD45横向结合，形成能够转导有效激活信号的多受体复合物。在这里，我们研究了gp120 / CD4结合改变CD4与其他淋巴细胞表面分子横向结合的可能性，以及异常多分子复合物的组装是否参与了gp120诱导的CD4 + T细胞功能障碍和病毒进入过程。在没有gp120的情况下，CD4与CD3、CD5、CD45RC、CD25、CD28、CD44和CD53高度结合；与CD2、CD38、CD45RB、CD62L和CD26弱结合；与CD45RA、CD45RO、CD11b、CD11a、CD54、CD7、CD48、CD98、CD59、CD55、HLA I类和II类分子无结合。用gp120处理显著增加了CD4与CD3、CD45RA、CD45RB、CD59、CD38、CD26和HLA I类的结合，并降低了与CD45RC的结合。这些结果的特异性在多个层面进行了评估。首先，gp120不影响其他分子如HLA II类所显示的横向结合。其次，结合CD4上与gp120结合位点重叠区域的Leu3单克隆抗体，不会引发与gp120相同的CD4横向结合，最后，如观察到Leu3单克隆抗体阻断gp120 / CD4结合会抑制gp120诱导的结合所示，需要直接的gp120 / CD4 +相互作用来诱导横向结合。这些结果可以有多种解释：gp120 / CD4相互作用可能触发一个负责结合的由外向内信号，或者gp120可以诱导CD4的空间修饰，增加其与结合分子的亲和力。或者，这些分子可能直接与gp120相互作用，将它们与CD4连接起来。也有可能这种结合是由其他成分介导的，这些成分与gp120和结合表面分子都相互作用。对于CD59，最后一种假设可能成立，其gp120诱导的与CD4的结合在共帽分析中需要血清的存在。由于CD59和gp120都结合补体，观察到的结合可能由补体成分介导。
