Mörner Andreas, Douagi Iyadh, Forsell Mattias N E, Sundling Christopher, Dosenovic Pia, O'Dell Sijy, Dey Barna, Kwong Peter D, Voss Gerald, Thorstensson Rigmor, Mascola John R, Wyatt Richard T, Karlsson Hedestam Gunilla B
Swedish Institute for Infectious Disease Control, Solna, Sweden.
J Virol. 2009 Jan;83(2):540-51. doi: 10.1128/JVI.01102-08. Epub 2008 Nov 12.
Currently there is limited information about the quality of immune responses elicited by candidate human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env)-based immunogens in primates. Here we describe a comprehensive analysis of neutralizing antibody and T-cell responses obtained in cynomolgus macaques by three selected immunization regimens. We used the previously described YU2-based gp140 protein trimers administered in an adjuvant, preceded by two distinct priming strategies: either alphavirus replicon particles expressing matched gp140 trimers or gp120 core proteins stabilized in the CD4-bound conformation. The rationale for priming with replicon particles was to evaluate the impact of the expression platform on trimer immunogenicity. The stable core proteins were chosen in an attempt to expand selectively lymphocytes recognizing common determinants between the core and trimers to broaden the immune response. The results presented here demonstrate that the platform by which Env trimers were delivered in the priming (either protein or replicon vector) had little impact on the overall immune response. In contrast, priming with stable core proteins followed by a trimer boost strikingly focused the T-cell response on the core sequences of HIV-1 Env. The specificity of the T-cell response was distinctly different from that of the responses obtained in animals immunized with trimers alone and was shown to be mediated by CD4(+) T cells. However, this regimen showed limited or no improvement in the neutralizing antibody responses, suggesting that further immunogen design efforts are required to successfully focus the B-cell response on conserved neutralizing determinants of HIV-1 Env.
目前，关于候选1型人类免疫缺陷病毒（HIV-1）包膜糖蛋白（Env）免疫原在灵长类动物中引发的免疫反应质量的信息有限。在此，我们描述了对食蟹猴通过三种选定免疫方案获得的中和抗体和T细胞反应的全面分析。我们使用了先前描述的基于YU2的gp140蛋白三聚体，在佐剂中给药，之前采用两种不同的启动策略：要么是表达匹配gp140三聚体的甲病毒复制子颗粒，要么是稳定在CD4结合构象的gp120核心蛋白。用复制子颗粒启动的基本原理是评估表达平台对三聚体免疫原性的影响。选择稳定的核心蛋白是为了选择性地扩增识别核心和三聚体之间共同决定簇的淋巴细胞，以扩大免疫反应。此处呈现的结果表明，在启动过程中递送Env三聚体的平台（无论是蛋白质还是复制子载体）对整体免疫反应影响不大。相比之下，先用稳定的核心蛋白启动，然后用三聚体加强免疫，显著地将T细胞反应集中在HIV-1 Env的核心序列上。T细胞反应的特异性与仅用三聚体免疫的动物所获得的反应明显不同，并且显示由CD4(+) T细胞介导。然而，该方案在中和抗体反应方面显示出有限的改善或没有改善，这表明需要进一步进行免疫原设计，以成功地将B细胞反应集中在HIV-1 Env的保守中和决定簇上。
