HIV-1 gp120-Conjugate Vaccines

描述（由申请方提供）：HIV-1包膜亚单位疫苗通常不能诱导针对HIV-1原代分离株的广泛交叉中和抗体。 一个可能的原因是覆盖gp 120表面的碳水化合物可能会阻碍有效的免疫识别/加工，从而限制中和表位的免疫识别。 该提案描述了将gp 120转化为更具免疫原性的分子的策略，该分子能够引发中和多种HIV-1原代分离株的抗体。 该提议有一个特定的目的，即检验由gp 120-cyanovirin复合物组成的模型疫苗将引发中和多种主要HIV-1分离株的抗体的假设，与不诱导这种中和抗体应答的未复合的gp 120相反。 氰核苷以高亲和力和特异性结合HIV-1 gp 120上的高甘露糖寡糖部分。 我们将用gp 120-CVN复合物免疫豚鼠，并评估损伤免疫应答。 提出CVN与gp 120复合将作为载体蛋白以几种可能的方式改变gp 120的免疫原性。 用小分子蛋白质包裹糖可以改善运输和加工。 其次，载体蛋白可以通过激活载体特异性T细胞来增强对gp 120的免疫力，这将有助于引发对gp 120的免疫原性较低的表位的应答。 第三个考虑因素是gp 120上的CD 4结合位点的免疫识别可能被gp 120与体内CD 4阳性细胞的结合所抑制。 已知氰核苷阻断可溶性gp 120与细胞CD 4的结合，并且这种性质可以允许更有效地呈递这组潜在重要的表位。 我们还将探索gp 120-CVN复合物诱导类似于HMAb 2G 12的抗体的可能性，该抗体识别在HIV感染患者中具有弱免疫原性的聚糖依赖性表位。

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.