NIH, NCI, 41 Medlars Drive, Building 41, Room D804, Bethesda, MD 20892-5065, USA.
J Virol. 2010 Jul;84(14):7161-73. doi: 10.1128/JVI.00410-10. Epub 2010 May 5.
We have shown that following priming with replicating adenovirus type 5 host range mutant (Ad5hr)-human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) recombinants, boosting with gp140 envelope protein enhances acute-phase protection against intravenous simian/human immunodeficiency virus (SHIV)(89.6P) challenge compared to results with priming and no boosting or boosting with an HIV polypeptide representing the CD4 binding site of gp120. We retrospectively analyzed antibodies in sera and rectal secretions from these same macaques, investigating the hypothesis that vaccine-elicited nonneutralizing antibodies contributed to the better protection. Compared to other immunized groups or controls, the gp140-boosted group exhibited significantly greater antibody activities mediating antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cell-mediated viral inhibition (ADCVI) in sera and transcytosis inhibition in rectal secretions. ADCC and ADCVI activities were directly correlated with antibody avidity, suggesting the importance of antibody maturation for functionality. Both ADCVI and percent ADCC killing prechallenge were significantly correlated with reduced acute viremia. The latter, as well as postchallenge ADCVI and ADCC, was also significantly correlated with reduced chronic viremia. We have previously demonstrated induction by the prime/boost regimen of mucosal antibodies that inhibit transcytosis of SIV across an intact epithelial cell layer. Here, antibody in rectal secretions was significantly correlated with transcytosis inhibition. Importantly, the transcytosis specific activity (percent inhibition/total secretory IgA and IgG) was strongly correlated with reduced chronic viremia, suggesting that mucosal antibody may help control cell-to-cell viral spread during the course of infection. Overall, the replicating Ad5hr-HIV/SIV priming/gp140 protein boosting approach elicited strong systemic and mucosal antibodies with multiple functional activities associated with control of both acute and chronic viremia.
我们已经证明，在对复制型 5 型腺病毒宿主范围突变体（Ad5hr）-人免疫缺陷病毒（HIV）/猴免疫缺陷病毒（SIV）重组体进行初步免疫接种后，用 gp140 包膜蛋白进行加强免疫接种可增强针对静脉内猴/人免疫缺陷病毒（SHIV）（89.6P）攻击的急性相保护作用，与仅进行初步免疫接种而不加强免疫或仅用代表 gp120 的 CD4 结合位点的 HIV 多肽进行加强免疫相比。我们对来自这些相同的猕猴的血清和直肠分泌物中的抗体进行了回顾性分析，调查了疫苗诱导的非中和抗体有助于更好保护的假设。与其他免疫接种组或对照组相比，gp140 加强免疫组在血清中介导抗体依赖性细胞毒性（ADCC）和抗体依赖性细胞介导的病毒抑制（ADCVI）以及直肠分泌物中的转胞吞抑制的抗体活性显著增加。ADCC 和 ADCVI 活性与抗体亲和力直接相关，这表明抗体成熟对功能的重要性。ADCC 杀伤的前挑战百分比和前挑战 ADCVI 与急性病毒血症减少显著相关。后者，以及后挑战 ADCVI 和 ADCC，也与慢性病毒血症减少显著相关。我们之前已经证明，由初级/加强方案诱导的粘膜抗体可抑制完整上皮细胞层中 SIV 的转胞吞作用。在这里，直肠分泌物中的抗体与转胞吞抑制显著相关。重要的是，转胞吞特异性活性（抑制百分比/总分泌性 IgA 和 IgG）与慢性病毒血症减少强烈相关，这表明粘膜抗体可能有助于控制感染过程中的细胞间病毒传播。总的来说，复制型 Ad5hr-HIV/SIV 初级/ gp140 蛋白加强免疫方案引发了具有多种功能活性的强烈系统性和粘膜抗体，这些活性与控制急性和慢性病毒血症均相关。
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