Wilson Nancy A, Keele Brandon F, Reed Jason S, Piaskowski Shari M, MacNair Caitlin E, Bett Andrew J, Liang Xiaoping, Wang Fubao, Thoryk Elizabeth, Heidecker Gwendolyn J, Citron Michael P, Huang Lingyi, Lin Jing, Vitelli Salvatore, Ahn Chanook D, Kaizu Masahiko, Maness Nicholas J, Reynolds Matthew R, Friedrich Thomas C, Loffredo John T, Rakasz Eva G, Erickson Stephen, Allison David B, Piatak Michael, Lifson Jeffrey D, Shiver John W, Casimiro Danilo R, Shaw George M, Hahn Beatrice H, Watkins David I
Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53711, USA.
J Virol. 2009 Jul;83(13):6508-21. doi: 10.1128/JVI.00272-09. Epub 2009 Apr 29.
All human immunodeficiency virus (HIV) vaccine efficacy trials to date have ended in failure. Structural features of the Env glycoprotein and its enormous variability have frustrated efforts to induce broadly reactive neutralizing antibodies. To explore the extent to which vaccine-induced cellular immune responses, in the absence of neutralizing antibodies, can control replication of a heterologous, mucosal viral challenge, we vaccinated eight macaques with a DNA/Ad5 regimen expressing all of the proteins of SIVmac239 except Env. Vaccinees mounted high-frequency T-cell responses against 11 to 34 epitopes. We challenged the vaccinees and eight naïve animals with the heterologous biological isolate SIVsmE660, using a regimen intended to mimic typical HIV exposures resulting in infection. Viral loads in the vaccinees were significantly less at both the peak (1.9-log reduction; P < 0.03) and at the set point (2.6-log reduction; P < 0.006) than those in control naïve animals. Five of eight vaccinated macaques controlled acute peak viral replication to less than 80,000 viral RNA (vRNA) copy eq/ml and to less than 100 vRNA copy eq/ml in the chronic phase. Our results demonstrate that broad vaccine-induced cellular immune responses can effectively control replication of a pathogenic, heterologous AIDS virus, suggesting that T-cell-based vaccines may have greater potential than previously appreciated.
迄今为止，所有的人类免疫缺陷病毒（HIV）疫苗效力试验均以失败告终。Env糖蛋白的结构特征及其巨大的变异性使得诱导具有广泛反应性的中和抗体的努力受挫。为了探究在没有中和抗体的情况下，疫苗诱导的细胞免疫反应能够在多大程度上控制异源黏膜病毒攻击的复制，我们用一种DNA/Ad5方案对8只猕猴进行了疫苗接种，该方案表达了除Env之外的SIVmac239的所有蛋白。接种疫苗的动物对11至34个表位产生了高频T细胞反应。我们使用一种旨在模拟导致感染的典型HIV暴露的方案，用异源生物分离株SIVsmE660对接种疫苗的动物和8只未接种疫苗的动物进行了攻击。接种疫苗的动物在峰值（降低1.9个对数；P < 0.03）和稳定期（降低2.6个对数；P < 0.006）的病毒载量均显著低于未接种疫苗的对照动物。8只接种疫苗的猕猴中有5只在急性期将峰值病毒复制控制在每毫升少于80,000个病毒RNA（vRNA）拷贝当量，在慢性期控制在每毫升少于100个vRNA拷贝当量。我们的结果表明，广泛的疫苗诱导细胞免疫反应可以有效控制致病性异源艾滋病病毒的复制，这表明基于T细胞的疫苗可能比以前认为的具有更大的潜力。
