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，覆盖在gp120表面的碳水化合物可能会阻碍有效的免疫识别/加工，从而限制免疫对中和表位的识别。该提案描述了将gp120转化为一种更具免疫原性的分子的策略，这种分子能够引发抗体，从而中和多种HIV-1原代分离物。这一建议有一个特定的目的，即测试由gp120-cyanovirin复合物组成的模型疫苗会引发抗体，从而中和多种原代HIV-1分离物，而不复杂的gp120则不会诱导这种中和抗体反应。Cyanovirin以高亲和力和特异性结合HIV-1 gp120上的高甘露糖低聚糖部分。我们将用gp120-CVN复合物免疫豚鼠并评估体液免疫反应。研究认为，CVN与gp120复合物可作为载体蛋白，通过多种途径改变gp120的免疫原性。用小蛋白质包住糖可以改善运输和加工。其次，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，这将有助于引发对gp120免疫原性较低的表位的反应。第三个考虑因素是gp120在体内与CD4阳性细胞的结合可能会抑制对gp120上CD4结合位点的免疫识别。已知Cyanovirin可以阻断可溶性gp120与细胞CD4的结合，这一特性可以更有效地呈递这组潜在的重要表位。我们还将探索gp120-CVN复合物诱导类似hab2g12的抗体的可能性，hab2g12可识别HIV感染患者中弱免疫原性的甘聚糖依赖性表位。

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.