HUMORAL AND CELLULAR IMMUNE RESPONSES TO HUMAN AND NONHUMAN PRIMATE RETROVIRUSES

使用活重组载体作为初免的联合艾滋病疫苗 载体随后蛋白质加强接种是有希望的。 腺病毒（Ad）-HIV-1（MN）包膜重组体，后接gp 120（SF 2 菌株）保护黑猩猩免受低剂量和高剂量的辐射 感染HIV-1（SF 2）。 重大进展包括： 要点：1）只需一次启动即可实现持久保护 免疫接种和2次蛋白加强，或2次引发和1次加强; 2） 高滴度中和抗体持续存在; 3） 一只受保护的黑猩猩缺乏中和抗体， HIV病毒特异性细胞毒性T淋巴细胞（CTL）受到保护， 低剂量攻击，首次表明CTL在 疫苗保护; 4）疫苗方案引起的抗体能够 中和原代分离株，之前未证实 其他方法; 5）对高剂量攻击的保护， 干预加强接种持续>50周。 的 所实现的保护仅来自于广告信封启动， GP 120增强。 加强保护将有望从类似的 方法整合HIV gag和nef基因和基因产物。 在猕猴中进行的进一步疫苗研究使用了Ad 5宿主范围突变体 携带SIV包膜基因的载体，与天然SIV 包膜亚单位 这种方法引起体液，细胞， 免疫猕猴的粘膜免疫应答。 黏膜免疫 尤其令人鼓舞的是，大约95%的艾滋病毒 全世界的传播都是通过粘膜屏障进行的。 的能力 这种疫苗方法可以预防阴道内和直肠内感染， 正在对传输进行评估。 类似的预充-增强方法有 使用减毒痘病毒载体作为疫苗 车辆. 早期的研究表明， 重组体和蛋白质导致对HIV-2的保护 挑战，这表明，发展一个单一的全球有效的 艾滋病疫苗可能是可能的。 我们正在扩大这项研究， 以前的结果，并确定交叉保护的性质 免疫力 最后，免疫逃逸变体的研究结果 强调了CD 4结合位点区域对包膜的关键作用， 功能和免疫识别。 我们已经证明， 来自CD 4结合位点区域的限制性螺旋肽 适当地对本机站点进行建模，并解释 HIV-1、HIV-2和SIV等不同的病毒如何识别 CD 4受体 使用这种螺旋肽的疫苗方法是 进行中。

Combination AIDS vaccines, using live recombinant vectors as priming vehicles followed by protein booster inoculations, are promising. Adenovirus (Ad)-HIV-1(MN) envelope recombinants followed by gp120 (SF2 strain) have protected chimpanzees from both low- and high-dose infection with HIV-1(SF2). Significant advances include the following points: 1) Long-lasting protection can be achieved with only 1 priming immunization and 2 protein boosters, or 2 primings and 1 booster; 2) the high-titered neutralizing antibodies elicited were persistent; 3) one protected chimpanzee lacking neutralizing antibodies but possessing HIV envelope-specific cytotoxic T-lymphocytes (CTL) was protected from low-dose challenge, suggesting for the first time a role for CTLs in vaccine protection; 4) the vaccine regimen elicited antibodies capable of neutralizing primary isolates, not previously demonstrated with other approaches; 5) protection against a high-dose challenge with no intervening booster inoculation persisted for >50 weeks. The protection that was achieved resulted from only Ad-envelope priming and gp120 boosting. Enhanced protection would be expected from a similar approach incorporating HIV gag and nef genes and gene products. Further vaccine studies in macaques have used an Ad 5 host range mutant vector carrying the SIV envelope gene, combined with a native SIV envelope subunit. This approach elicited humoral, cellular, and mucosal immune responses in immunized macaques. The mucosal immunity is particularly encouraging, as approximately 95% of all HIV transmissions worldwide occur across mucosal barriers. The ability of this vaccine approach to protect against intravaginal and intrarectal transmission is being evaluated. Similar prime-boost approaches are being carried out using attenuated poxvirus vectors as vaccine vehicles. Earlier studies showed that immunization with HIV-1 recombinants and proteins resulted in protection against HIV-2 challenge, suggesting that development of a single globally effective AIDS vaccine might be possible. We are expanding this study to confirm the previous result and identify the nature of the cross-protective immunity. Finally, results of studies on immune escape variants have highlighted the CD4 binding site region as crucial for envelope function and immune recognition. We have shown that a conformationally constrained helical peptide from the CD4 binding site region appropriately models the native site and provides an explanation for how such disparate viruses, as HIV-1, HIV-2, and SIV, can all recognize the CD4 receptor. Vaccine approaches using this helical peptide are in progress.