Vectored delivery of anti-HIV antibodies for mucosal protection

项目总结/摘要 HIV包膜刺突的不良免疫原性及其巨大的变异性代表了有效免疫的主要障碍。 激发保护性抗HIV抗体。一个有希望的策略是绕过免疫系统， 已知的和充分表征的直接针对宿主的有效和广泛中和的抗体。然而，在这方面， 需要定期给予大量蛋白质以获得长期效果。重组腺病毒 相关病毒（AAV）载体由于其安全性和生物相容性而广泛用于基因递送应用。 成本效率：一次注射可以解释转基因的长期表达。使用AAV 载体将绕过定期施用抗体的需要，并且只要递送的蛋白质是 作为自我，它可以导致持续持久的表达。对猴子和老鼠的研究已经 展示了AAV用于这种抗HIV抗体递送方法的极端前景， 证明了它的安全性和可行性。然而，只有IgG形式的抗体（单体免疫球蛋白） 已经用于这种AAV-抗体递送应用，而聚合免疫球蛋白（例如 二聚体伊加和五聚体IgM）被忽视，尽管它们具有粘膜免疫的理想特性。 保护此外，关于循环中AAV递送的抗体被转移的比例知之甚少。 相关的病毒进入点，如直肠或阴道粘膜，以及如何与水平相关， 可以实现的对粘膜暴露的保护。基于我们之前的猴子试验，我们 本文提出的是评估AAV介导的有效和广泛中和抗体的递送， 免疫球蛋白的类型，并评估保护程度，可以达到粘膜病毒的挑战， 每种类型（目标1）。我们将使用高度相关的猕猴模型并定量体内AAV产生的抗体 在循环和相关粘膜中。我们的目标是找到哪种免疫球蛋白类型显示最佳转移 的AAV递送的抗体对粘膜中的病毒进入点和/或针对攻击的最佳保护。 由于艾滋病毒主要通过性传播，我们的发现将与抗击艾滋病毒的斗争高度相关 传输我们的总体目标是告知和指导AAV抗体概念的开发，以用于 人

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.