Breadth of Neutralizing Antibodies Elicited by Stable, Homogeneous Clade A and Clade C HIV-1 gp140 Envelope Trimers in Guinea Pigs
Breadth of Neutralizing Antibodies Elicited by Stable, Homogeneous Clade A and Clade C HIV-1 gp140 Envelope Trimers in Guinea Pigs
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DOI：
10.1128/jvi.02252-09
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发表时间：
2010-04-01
影响因子：
5.4
通讯作者：
Barouch, Dan H.
中科院分区：
文献类型：
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作者：
Nkolola, Joseph P.;Peng, Hanqin;Barouch, Dan H.
人类免疫缺陷病毒1型（HIV-1）表面的天然包膜（Env）刺突是三聚体的，因此三聚体Env疫苗免疫原目前正在临床前免疫原性研究中进行探索。主要挑战包括生产和纯化生化均质和稳定的三聚体，以及利用标准化病毒板进行中和试验对这些免疫原进行评估。本文报道了进化枝A （92UG037.8）和进化枝C (CZA97.012) Env gp140三聚体免疫原在豚鼠体内引发的结合和中和抗体（NAb）反应。这些三聚体已被选择和工程化，以获得最佳的生化稳定性，并具有明确的抗原特性。用Ribi佐剂纯化的gp140三聚体可激发针对1级病毒的强效、跨分支的NAb反应，以及针对A、B和C分支中选定的2级病毒的可检测但低滴度的NAb反应。特别是，C分支三聚体所激发的NAb可分别中和来自A、B和C分支的27%、20%和47%的2级病毒。然而，表达这些抗原的异源DNA引物、蛋白质增强以及DNA引物、重组腺病毒增强方案并未导致该系统中NAb反应的幅度或广度增加。这些数据证明了稳定、均匀的A和C分支gp140三聚体的免疫原性，并举例说明了标准化的1级和2级病毒组用于评估候选HIV-1 Env免疫原的NAb反应的效用。
The native envelope (Env) spike on the surface of human immunodeficiency virus type 1 (HIV-1) is trimeric, and thus trimeric Env vaccine immunogens are currently being explored in preclinical immunogenicity studies. Key challenges have included the production and purification of biochemically homogeneous and stable trimers and the evaluation of these immunogens utilizing standardized virus panels for neutralization assays. Here we report the binding and neutralizing antibody (NAb) responses elicited by clade A (92UG037.8) and clade C (CZA97.012) Env gp140 trimer immunogens in guinea pigs. These trimers have been selected and engineered for optimal biochemical stability and have defined antigenic properties. Purified gp140 trimers with Ribi adjuvant elicited potent, cross-clade NAb responses against tier 1 viruses as well as detectable but low-titer NAb responses against select tier 2 viruses from clades A, B, and C. In particular, the clade C trimer elicited NAbs that neutralized 27%, 20%, and 47% of tier 2 viruses from clades A, B, and C, respectively. Heterologous DNA prime, protein boost as well as DNA prime, recombinant adenovirus boost regimens expressing these antigens, however, did not result in an increased magnitude or breadth of NAb responses in this system. These data demonstrate the immunogenicity of stable, homogeneous clade A and clade C gp140 trimers and exemplify the utility of standardized tier 1 and tier 2 virus panels for assessing the NAb responses of candidate HIV-1 Env immunogens.