NEUTRALIZING RESPONSES TO HIV GP120 COMPLEXED WITH CD4 A

我们建议研究特定配体对抗原的影响。 处理和呈现以及关于 产生对HIV包膜蛋白和细胞的抗体反应 病毒的受体。这项研究的最终目标是调节 为了获得更高比例的抗体，能够 在任何阶段通过任何机制中和病毒和/或阻止病毒 膜融合的过程，使病毒能够穿透 目标单元格。根据我们之前在一个非相关系统中的研究， 针对抗原关键部位的单抗是首选 影响摄取、加工和呈递的大分子配体 T细胞。我们将用HIV gp120免疫动物(小鼠、兔子)。 不同单抗与包膜蛋白的复合作用 已知表位，并确定了良好的特异性和功能性 由此产生的细胞和抗体反应的特征。在……里面 并行地，利用gp120和gp120之间的结合 可溶性形式的重组cd4具有特异性和亲和力。 强免疫相互作用(Ko=10-9n)，我们目前正在确定 触发免疫反应的数量效应和质量效应 通过注射复合的和游离的CD4和gp120。我们目前的情况 该系统的结果显示联会阻断效价异常高。 在小鼠和兔体内注射CD4-gp120。出现封闭抗体 被定向到CD4部分，并在第一次接触后采取行动 病毒与细胞受体的包膜已经发生。我们将分析 利用单抗中和HIV的新机制 CD_4-gp_(120)复合体免疫小鼠的抗体及其检测 假设a)发生了一系列构象转变 Gp160以及在CD4中，发现或产生易感结构 中和抗体，以及b)这种新抗原定位于 受体可以是免疫原性的，即使天然的CD_4是“自身”分子， 例如在灵长类动物和人类身上。

We propose to investigate the influence of specific ligands on the antigen processing and presentation as well as on the fine specificities of the resulting antibody response to the HIV envelope proteins and the cellular receptors for the virus. The final goal of this study is to modulate the response in order to obtain higher proportions of antibodies capable of neutralizing the virus and/or blocking at any stage and by any mechanism the process of membrane fusion which allows the virus to penetrate the target cell. According to our previous studies in a non related system, monoclonal antibodies directed to critical sites of the antigen are choice macromolecular ligands for influencing uptake, processing and presentation to T cells. We shall immunize animals (mice, rabbits) with HIV gp120 envelope protein complexed with different monoclonal antibodies directed at known epitopes, and determine the fine specificity and functional characteristics of the resulting cellular and antibody responses. In parallel, taking advantage of the fact that the binding between gp120 and recombinant CD4 in soluble form has the specificity and the affinity of a strong immune interaction (Ko = 10-9n), we are presently determining the quantitative and the qualitative effects of triggering the immune response by the injection of complexed versus free CD4 and gp120. Our current results in this system show an exceptionally high syncitia-blocking titer in mice and rabbits injected with CD4-gp120. The blocking antibody appears to be directed to the CD4 moiety, and to act after the first contact of the viral envelope with the cell receptor has taken place. We shall analyze this novel mechanism of HIV neutralization by means of monoclonal antibodies obtained from the mice immunized with CD4-gp120 complex and test the hypotheses a) that a number of conformational transitions take place in gp160 as well as in CD4, uncovering or generating structures susceptible to neutralizing antibodies, and b) that such neoantigens localized in the receptor can be immunogenic even when the native CD4 is "self" molecule, e.g. in primates and man.