Non-human Primate Immunogenicity Studies of HIV-1 immunogens

HIV-1包膜糖蛋白（Env）的遗传多样性仍然是开发基于抗体的艾滋病疫苗的主要障碍。本研究检测了恒河猴在接种编码单个或多个遗传上遥远的Env免疫原的DNA引物重组腺病毒（rAd）增强疫苗后，随后用致病性猿人免疫缺陷病毒（SHIV-89.6P）刺激后，中和抗体（NAb）反应的广度和强度。使用标准的多层参考Env假病毒进行NAb评估，我们发现，与单一Env免疫原（分支B或C）免疫的猴子相比，接种混合Env免疫原（分支a、B和C）免疫的猴子在接种和攻击后对中和敏感的第1层病毒表现出更广泛的NAb活性。然而，所有接种env疫苗的猴子对Tier 2假病毒的中和活性都有限，Tier 2假病毒更具有循环HIV-1的中和敏感性。值得注意的是，在接受B支、C支或a +B+C支Env免疫原的猴子中，针对SHIV-89.6P的攻击后NAb反应的发展是相似的，这表明NAb反应是跨支启动的。此外，与缺乏Env成分的疫苗相比，编码SHIV-89.6P异种Env免疫原的疫苗可在感染后引发快速的遗忘性NAb反应。这些结果表明，用多种不同的Env免疫原进行DNA/rAd免疫是提高NAb对HIV-1反应广度的可行方法，并表明Env免疫原可以启动针对异源攻击病毒的记忆性NAb反应。

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.