Host Anti-antibody Responses Following Adeno-associated Virus-mediated Delivery of Antibodies Against HIV and SIV in Rhesus Monkeys
Host Anti-antibody Responses Following Adeno-associated Virus-mediated Delivery of Antibodies Against HIV and SIV in Rhesus Monkeys
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DOI：
10.1038/mt.2015.191
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发表时间：
2016-01-01
影响因子：
12.4
通讯作者：
Desrosiers, Ronald C.
中科院分区：
文献类型：
--
作者：
Martinez-Navio, Jose M.;Fuchs, Sebastian P.;Desrosiers, Ronald C.
使用腺相关病毒（AAV）载体长期递送针对人类免疫缺陷病毒（HIV）的抗体是用于预防或治疗HIV感染的有希望的方法。然而，宿主抗体对递送的抗体的反应是一个严重的问题，这可能会显著限制这种方法的适用性。在这里，我们描述了在预防试验中接受恒河猴抗猴免疫缺陷病毒（SIV）抗体（4L 6或5L 7）或在治疗试验中接受恒河猴化人抗HIV抗体（1 NC 9/8ANC 195/3BNC 117或10-1074/10 E8/3BNC 117）组合的猴中抗抗体应答的动力学和特征，所有这些均采用AAV 1递送IgG 1。接受抗HIV抗体的8只猴子中有8只对混合物中的所有三种抗体产生持续的抗体反应。接受抗SIV抗体4L 6的6只未感染猴子中的6只和接受抗SIV抗体5L 7的6只猴子中的3只也产生抗抗体。重链和轻链均主要或专门靶向可变区，并且可以证明与互补决定区（CDR）-H3肽的反应性。抗抗体应答的幅度与来自生殖系的递送抗体的序列差异程度高度显著相关。我们的研究结果表明，需要有效的策略，以抵消的问题，抗体反应的AAV-交付的抗体。
Long-term delivery of antibodies against the human immunodeficiency virus (HIV) using adeno-associated virus (AAV) vectors is a promising approach for the prevention or treatment of HIV infection. However, host antibody responses to the delivered antibody are a serious concern that could significantly limit the applicability of this approach. Here, we describe the dynamics and characteristics of the anti-antibody responses in monkeys that received either rhesus anti-simian immunodeficiency virus (SIV) antibodies (4L6 or 5L7) in prevention trials or a combination of rhesusized human anti-HIV antibodies (1NC9/8ANC195/3BNC117 or 10-1074/10E8/3BNC117) in therapy trials, all employing AAV1 delivery of IgG1. Eight out of eight monkeys that received the anti-HIV antibodies made persisting antibody responses to all three antibodies in the mix. Six out of six uninfected monkeys that received the anti-SIV antibody 4L6 and three out of six of those receiving anti-SIV antibody 5L7 also generated anti-antibodies. Both heavy and light chains were targeted, predominantly or exclusively to variable regions, and reactivity to complementarity-determining region (CDR)-H3 peptide could be demonstrated. There was a highly significant correlation of the magnitude of anti-antibody responses with the degree of sequence divergence of the delivered antibody from germline. Our results suggest the need for effective strategies to counteract the problem of antibody responses to AAV-delivered antibodies.