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。 目前的研究检查的宽度和幅度的中和抗体（NAb）的反应后，恒河猴的DNA引物重组腺病毒（rAd）加强疫苗免疫编码的单一或多个遗传上遥远的Env免疫原，随后挑战的致病性猴-人类免疫缺陷病毒（SHIV-89.6P）。 使用标准化的多层参考Env假病毒组进行NA B评估，我们表明，与用单一Env免疫原（进化枝B或C）免疫的猴相比，用Env免疫原混合物（进化枝A、B和C）免疫的猴在疫苗接种和攻毒后对中和敏感的1级病毒表现出更大的NA B活性。 然而，所有Env疫苗接种猴组均仅表现出有限的2级假病毒中和活性，这更具有循环HIV-1中和敏感性的特征。 值得注意的是，在接受进化枝B、进化枝C或进化枝A+B+C Env免疫原的猴中，针对SHIV-89.6 P的攻击后NA B应答的发展相似，表明NA B应答的交叉进化枝引发。 此外，与缺乏Env组分的疫苗相比，编码与SHIV-89.6P异源的Env免疫原的疫苗在感染后引发快速回忆性NAb应答。 这些结果表明，DNA/rAd免疫与多种不同的Env免疫原是一种可行的方法，用于提高针对HIV-1的NAb应答的广度，并表明Env免疫原可以引发针对异源攻击病毒的回忆性NAb应答。

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.