Seaman Michael S, Leblanc Daniel F, Grandpre Lauren E, Bartman Melissa T, Montefiori David C, Letvin Norman L, Mascola John R
Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, 330 Brookline Ave/RE-204, Boston, MA 02215, USA.
Virology. 2007 Oct 10;367(1):175-86. doi: 10.1016/j.virol.2007.05.024. Epub 2007 Jun 27.
The genetic diversity of HIV-1 envelope glycoproteins (Env) remains a major obstacle to the development of an antibody-based AIDS vaccine. The present studies examine the breadth and magnitude of neutralizing antibody (NAb) responses in rhesus monkeys after immunization with DNA prime-recombinant adenovirus (rAd) boost vaccines encoding either single or multiple genetically distant Env immunogens, and subsequently challenged with a pathogenic simian-human immunodeficiency virus (SHIV-89.6P). Using a standardized multi-tier panel of reference Env pseudoviruses for NAb assessment, we show that monkeys immunized with a mixture of Env immunogens (clades A, B, and C) exhibited a greater breadth of NAb activity against neutralization-sensitive Tier 1 viruses following both vaccination and challenge compared to monkeys immunized with a single Env immunogen (clade B or C). However, all groups of Env-vaccinated monkeys demonstrated only limited neutralizing activity against Tier 2 pseudoviruses, which are more characteristic of the neutralization sensitivity of circulating HIV-1. Notably, the development of a post-challenge NAb response against SHIV-89.6P was similar in monkeys receiving either clade B, clade C, or clade A+B+C Env immunogens, suggesting cross-clade priming of NAb responses. In addition, vaccines encoding Env immunogens heterologous to SHIV-89.6P primed for a rapid anamnestic NAb response following infection compared to vaccines lacking an Env component. These results show that DNA/rAd immunization with multiple diverse Env immunogens is a viable approach for enhancing the breadth of NAb responses against HIV-1, and suggest that Env immunogens can prime for anamnestic NAb responses against a heterologous challenge virus.
HIV-1包膜糖蛋白（Env）的基因多样性仍然是基于抗体的艾滋病疫苗研发的主要障碍。本研究检测了恒河猴在用编码单个或多个基因距离较远的Env免疫原的DNA初免-重组腺病毒（rAd）加强疫苗免疫后，以及随后用致病性猿猴-人类免疫缺陷病毒（SHIV-89.6P）攻击后的中和抗体（NAb）反应的广度和强度。使用标准化的多层参考Env假病毒面板进行NAb评估，我们发现，与用单一Env免疫原（B或C亚型）免疫的猴子相比，用Env免疫原混合物（A、B和C亚型）免疫的猴子在疫苗接种和攻击后对中和敏感的1级病毒表现出更大广度的NAb活性。然而，所有接种Env疫苗的猴子组对2级假病毒仅表现出有限的中和活性，2级假病毒更能体现循环HIV-1的中和敏感性特征。值得注意的是，接受B亚型、C亚型或A+B+C亚型Env免疫原的猴子在攻击后针对SHIV-89.6P的NAb反应的发展相似，表明NAb反应存在跨亚型启动。此外，与缺乏Env成分的疫苗相比，编码与SHIV-89.6P异源的Env免疫原的疫苗在感染后引发了快速的回忆性NAb反应。这些结果表明，用多种不同的Env免疫原进行DNA/rAd免疫是增强针对HIV-1的NAb反应广度的可行方法，并表明Env免疫原可以引发针对异源攻击病毒的回忆性NAb反应。
