NEUTRALIZING RESPONSES TO HIV GP120 COMPLEXED WITH CD4 A

我们建议研究特异性配体对抗原的影响 处理和介绍以及对优良的具体性， 所产生的抗体对HIV包膜蛋白和细胞膜蛋白的反应， 病毒的受体 本研究的最终目的是调节 为了获得更高比例的抗体， 中和病毒和/或在任何阶段通过任何机制阻断 膜融合的过程，使病毒能够穿透 靶细胞。 根据我们以前在非相关系统中的研究， 选择针对抗原关键位点的单克隆抗体 影响摄取、加工和呈递的大分子配体 to T cells细胞. 我们将用HIV gp 120免疫动物（小鼠、兔子） 与不同单克隆抗体复合的包膜蛋白， 已知的表位，并确定精细的特异性和功能 结果细胞和抗体反应的特征。 在 平行，利用gp 120和 可溶性形式的重组CD 4具有特异性和亲和性， 强免疫相互作用（Ko = 10- 9 n），我们目前正在确定 触发免疫反应的定量和定性影响 通过注射复合的与游离的CD 4和gp 120。 我们目前 该系统的结果显示出异常高的合胞体阻断滴度 在注射了CD 4-gp 120的小鼠和兔子中。 封闭抗体出现了 被导向CD 4部分，并在第一次接触CD 4部分后起作用。 病毒包膜与细胞受体发生了相互作用。 我们将分析 这种通过单克隆抗体中和HIV的新机制 从用CD 4-gp 120复合物免疫的小鼠获得的抗体和测试 假设a）在一个特定的时间段内发生了许多构象转变， gp 160以及CD 4中，发现或产生易受影响的结构 中和抗体，和B）所述新抗原定位于所述细胞中， 受体可以是免疫原性的，甚至当天然CD 4是“自身”分子时， 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.