HIV-1 gp120-Conjugate Vaccines

描述(由申请人提供)：HIV-1包膜亚单位疫苗通常不能诱导针对主要HIV-1分离株的广泛交叉中和抗体。一个可能的原因是覆盖在gp120表面的碳水化合物可能会阻碍有效的免疫识别/处理，从而限制中和表位的免疫识别。这项建议描述了将gp120转化为一种更具免疫原性的分子的策略，该分子能够诱导抗体，中和多种HIV-1初级分离株。这项提议有一个具体的目标，那就是检验这样一种假设，即由gp120-氰基韦林复合体组成的模型疫苗将产生抗体，中和多种初级HIV-1分离株，而不是不复杂的gp120，后者不会诱导这种中和抗体反应。氰韦林与HIV-1gp120上的高甘露糖低聚糖部分具有高亲和力和特异性。我们将用gp120-CVN复合体免疫豚鼠，并评估伤害性免疫反应。有人认为，与gp120结合的CVN将作为载体蛋白通过几种可能的方式改变gp120的免疫原性。在糖上涂上一种小蛋白质可能会改善运输和加工。第二，载体蛋白可能通过激活载体特异性T细胞来增强对gp120的免疫力，这将有助于激发对gp120免疫原性较低的表位的反应。第三个考虑是，在体内，gp120与CD4阳性细胞的结合可能会抑制对gp120上CD4结合部位的免疫识别。已知氰化韦林能阻断可溶性gp120与细胞内CD4的结合，这一特性可能允许更有效地呈现这组潜在的重要表位。我们还将探索gp120-CVN复合体诱导类似于HMAb2G12的抗体的可能性，HMAb2G12识别HIV感染患者中弱免疫原性的糖依赖表位。

DESCRIPTION (provided by applicant): HIV-1 envelope subunit vaccines generally fail to induce broadly cross-neutralizing antibodies against primary HIV-1 isolates. One possible reason is that carbohydrates covering the surface of gp120 may block efficient immune recognition/processing, thereby limiting immune recognition of neutralization epitopes. This proposal describes strategies to convert gp120 into a more immunogenic molecule capable of eliciting antibodies that neutralize a diversity of HIV-1 primary isolates. This proposal has one specific aim which is to test the hypothesis that a model vaccine consisting of gp120-cyanovirin complexes will elicit antibodies that neutralize a diversity of primary HIV-1 isolates in contrast to uncomplexed gp120, which does not induce such neutralizing antibody responses. Cyanovirin binds with high affinity and specificity to high mannose oligosaccharide moieties on HIV-1 gp120. We will immunize guinea pigs with gp120-CVN complexes and assess hurmoral immune responses. It is proposed that CVN complexed to gp120 will function as a carrier protein to change the immunogenicity of gp120 in several possible ways. Coating the sugars with a small protein may improve transport and processing. Secondly, the carrier protein may enhance immunity to gp120 by activating carrier-specific T cells will provide help in eliciting responses to less immunogenic epitopes of gp120. A third consideration is that immune recognition of the CD4 binding site on gp120 may be dampened by the binding of gp120 to CD4 positive cells in vivo. Cyanovirin is known to block binding of soluble gp120 to cellular CD4 and this property may allow more efficient presentation this potentially important group of epitopes. We will also explore the possibility that gp120-CVN complexes will induce antibodies similar to the HMAb2G12 which recognizes a glycan-dependent epitope that is weakly immunogenic in HIV infected patients.