Department of Virology and Immunology, Texas Biomedical Research Institute.
Department of Microbiology, Immunology & Molecular Genetics, The University of Texas Health Science Center at San Antonio.
AIDS. 2018 Jul 17;32(11):F5-F13. doi: 10.1097/QAD.0000000000001857.
Worldwide, most new HIV infections occur through mucosal exposure. Immunoglobulin M (IgM) is the first antibody class generated in response to infectious agents; IgM is present in the systemic circulation and in mucosal fluids as secretory IgM. We sought to investigate for the first time the role of IgM in preventing AIDS virus acquisition in vivo.
Recombinant polymeric monoclonal IgM was generated from the neutralizing monoclonal IgG1 antibody 33C6-IgG1, tested in vitro, and given by passive intrarectal immunization to rhesus macaques 30 min before intrarectal challenge with simian-human immunodeficiency virus (SHIV) that carries an HIV-1 envelope gene.
In vitro, 33C6-IgM captured virions more efficiently and neutralized the challenge SHIV with a 50% inhibitory molar concentration (IC50) that was 1 log lower than that for 33C6-IgG1. The IgM form also exhibited significantly higher affinity and avidity compared with 33C6-IgG1. After intrarectal administration, 33C6-IgM prevented viremia in four out of six rhesus macaques after high-dose intrarectal SHIV challenge. Five out of six rhesus macaques given 33C6-IgG1 were protected at a five times higher molar concentration compared with the IgM form; all untreated controls became highly viremic. Rhesus macaques passively immunized with 33C6-IgM with breakthrough infection had notably early development of autologous neutralizing antibody responses.
Our primate model data provide the first proof-of-concept that mucosal IgM can prevent mucosal HIV transmission and have implications for HIV prevention and vaccine development.
在全球范围内，大多数新的 HIV 感染都是通过黏膜接触发生的。免疫球蛋白 M（IgM）是针对感染因子产生的第一类抗体；IgM 存在于全身循环和黏膜液中作为分泌型 IgM。我们首次试图研究 IgM 在体内预防艾滋病病毒感染中的作用。
从中和性单克隆 IgG1 抗体 33C6-IgG1 中产生重组多克隆单克隆 IgM，进行体外测试，并在直肠内接受 simian-human 免疫缺陷病毒（SHIV）攻击前 30 分钟通过被动直肠内免疫接种给予恒河猴，该病毒携带 HIV-1 包膜基因。
在体外，33C6-IgM 更有效地捕获病毒粒子，并以比 33C6-IgG1 低 1 个对数的 50%抑制摩尔浓度（IC50）中和挑战 SHIV。IgM 形式还表现出与 33C6-IgG1 相比显著更高的亲和力和亲和力。直肠内给药后，在高剂量直肠内 SHIV 攻击后，6 只恒河猴中有 4 只预防了病毒血症。与 IgM 形式相比，给予 33C6-IgG1 的 6 只恒河猴中有 5 只得到了更高的保护，而所有未经治疗的对照组均出现高病毒血症。在突破感染中被动免疫接种 33C6-IgM 的恒河猴明显早地发展出自体中和抗体反应。
我们的灵长类动物模型数据首次提供了黏膜 IgM 可预防黏膜 HIV 传播的概念验证，并对 HIV 预防和疫苗开发具有重要意义。
