Preclinical Evaluation Of Neutralizing Antibodies Elicited by 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。本研究检测了用编码单个或多个遗传距离较远的Env免疫原的DNA基元-重组腺病毒(Rad)Boost疫苗免疫恒河猴后，恒河猴中和抗体(NAB)反应的广度和幅度，并随后用致病性猴-人类免疫缺陷病毒(SIV-89.6P)攻击。使用标准的多层参考Env伪病毒小组进行NAB评估，我们表明，与用单一Env免疫原(分支B或C)免疫的猴子相比，用混合Env免疫原(分支A、B和C)免疫的猴子在接种疫苗和攻击后对中和敏感的Tier 1病毒表现出更大的NAB活性。然而，所有接种了Env疫苗的猴子对Tier 2伪病毒的中和活性都是有限的，而Tier 2伪病毒更具有循环中和HIV-1的敏感性。值得注意的是，在接受分支B、分支C或分支A+B+C环境免疫原的猴子中，针对SHV-89.6P的攻击后NAB反应的发展类似，这表明NAB反应的交叉启动。此外，与没有Env成分的疫苗相比，编码与SIV-89.6P异源的Env免疫原的疫苗可以在感染后快速记忆NAB反应。这些结果表明，用多种不同的环境免疫原进行DNA/Rad免疫是提高针对HIV-1的NAB反应广度的一种可行的方法，并提示环境免疫原可以启动对异源挑战病毒的记忆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.