Vectored delivery of anti-HIV antibodies for mucosal protection

项目摘要/摘要 HIV包膜尖峰的低免疫原性及其巨大的变异性是高效的主要障碍 保护性抗HIV抗体的诱导。一种有希望的策略是绕过免疫系统并提供 已知的、特征明确的直接针对宿主的强效和广谱中和抗体。然而， 需要定期服用大量蛋白质才能产生长期效果。重组腺病毒- 相关病毒(AAV)载体因其安全性和安全性而被广泛用于基因递送应用 成本效益：一次注射可以解释转基因的长期表达。AAV的使用 载体将绕过定期注射抗体的需要，只要交付的蛋白质是 作为自我，它可以带来持续持久的表达。在猴子和老鼠身上进行的研究已经 展示了AAV在这种对抗艾滋病毒的抗体传递方法中的极端前景，并开创了人类试验的先河 已经证明了其安全性和可行性。然而，只有免疫球蛋白形式的抗体(单体免疫球蛋白) 已经被用于这种AAV抗体递送应用，而聚合物免疫球蛋白(例如 二聚体免疫球蛋白A和五聚体免疫球蛋白M)被忽视，尽管它们对粘膜具有理想的特性 保护。此外，人们对AAV传递的循环抗体的转移比例知之甚少。 与相关的病毒进入点，如直肠或阴道粘膜，以及这与水平的相关性 可实现的对黏膜暴露的保护。在我们之前的猴子试验的基础上，我们 这里提出的是评价AAV介导的有效和广谱中和抗体的传递不同于 免疫球蛋白类型，并评估通过以下方法可实现的对黏膜病毒攻击的保护程度 每种类型(目标1)。我们将使用高度相关的猕猴模型，并在体内定量AAV产生的抗体 在循环中和相关的粘膜中。我们的目标是找出哪种免疫球蛋白类型显示最佳转移 AAV递送的针对粘膜病毒入口点的抗体和/或针对攻击的最佳保护。 由于艾滋病毒主要通过性传播，我们的发现将在抗击艾滋病毒方面具有很高的相关性 变速箱。我们的总体目标是告知和指导AAV抗体概念的发展，以便在 人民。

Project Summary/Abstract The poor immunogenicity of the HIV envelope spike and its vast variability represent major obstacles for efficient elicitation of protective anti-HIV antibodies. One promising strategy is to bypass the immune system and deliver already known and well-characterized potent and broadly neutralizing antibodies directly to the host. However, periodic administrations of large amounts of protein would be required for long-term effects. Recombinant adeno- associated virus (AAV) vectors have been widely used for gene delivery applications because of their safety and cost-efficiency: one single injection can account for long term expression of the transgene. The use of AAV vectors would bypass the need for periodic administrations of antibody and, as long as the delivered protein is viewed as self, it can result in continuous durable expression. Studies in monkeys and in mice have already shown the extreme promise of AAV for this antibody delivery approach against HIV, and pioneer human trials have demonstrated its safety and feasibility. However, only antibodies in IgG form (monomeric immunoglobulin) have been employed in such AAV-antibody delivery applications, while polymeric immunoglobulins (such as dimeric IgA and pentameric IgM) have been overlooked, despite their desirable characteristics for mucosal protection. In addition, little is known about what proportion of circulating AAV-delivered antibody gets transferred to relevant viral entry points such as the rectal or vaginal mucosae and how that correlates with the level of protection against mucosal exposure that can be achieved. Building up on our previous monkey trials, what we propose here is to evaluate AAV-mediated delivery of a potent and broadly neutralizing antibody as different immunoglobulin types and assess the degree of protection that can be achieved to mucosal viral challenge by each type (Aim 1). We will use the highly relevant macaque model and quantitate in vivo AAV-produced antibody in circulation and in the relevant mucosae. Our goal is to find what immunoglobulin type shows optimal transfer of the AAV-delivered antibody to the viral point of entry in mucosae and/or optimal protection against challenge. Because HIV is mainly transmitted sexually, our findings will be highly relevant in the fight against HIV transmission. Our overall goal is to inform and guide development of the AAV-antibody concept for its use in people.