Optimizing Plantibodies for Trapping HIV and HSV in Cervovaginal Mucus

优化 Plantibodies 以捕获子宫颈阴道粘液中的 HIV 和 HSV

• 批准号: 8515325
• 负责人: RICHARD CONE
• 金额: $ 15.37万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8515325
• 关键词: Acquired Immunodeficiency Syndrome; Adhesives; Affinity; Antibodies; Binding; Blood; Cells; Complement Activation; Diffuse; Dose; Epithelial; Film; Gel; Genital system; HIV; Herpesvirus 1; Human; Immune system; Immunoglobulin G; Infection; Lymph; Methods; Monoclonal Antibodies; Mucous body substance; Plantibodies; Plants; Safety; Seminal fluid; Simplexvirus; Surface; Testing; Vagina; Vaginal Ring; Viral; Virion; Virus; Virus-like particle; base; cervicovaginal; crosslink; design; genital herpes; immune function; in vivo; microbicide; vaginal microbicide; vaginal transmission

For vaginal transmission, viruses must penetrate mucus secretions to reach target cells; we recentiy found that Herpes Simplex Virus (HSV) and HIV readily diffuses through human cervicovaginal mucus. Most antibodies (Ab) produced by the immune system are secreted into mucus (not blood or lymph), and topical IgG provides robust protection against vaginal viral challenges. In addition to well-known antibody functions (e.g., neutralization, complement activation, opsonization), an important yet little recognized effector function of IgG is to trap viruses in mucus. IgG bound to a virus surface may form multiple low-affinity adhesive crosslinks between the virus and the mucus gel. A sufficient number of these low-affinity crosslinks, possibly at sub-neutralizing IgG concentrations, may permanently trap the virus in the mucus gel. Our pilot observations indicate that remarkably low concentrations of specific IgGI can trap HSV-1 and virus-like particles that otherwise rapidly penetrate mucus gels. Trapping reduces the flux of virus that reaches target cells, and facilitates inactivation and clearance by additional protective mechanisms. Trapping viruses in mucus before they can reach target cells is likely essential to protect against viruses that, once established, cause incurable infections. It is likely that the most protective antibodies will be those that not only neutralize virions by blocking viral entry into target cells, but also are highly effective at trapping virions in mucus. This potential IgG trapping function in mucus has been largely unrecognized because most studies of IgG activity have not been performed in mucus geis. Hence, all monoclonal antibodies (MAbs) developed to date has been developed without considering this immune function in mucus.

对于阴道传播，病毒必须穿透粘液分泌物才能到达目标细胞；我们最近发现 单纯疱疹病毒 (HSV) 和 HIV 很容易通过人类宫颈阴道粘液传播。大多数抗体 免疫系统产生的 (Ab) 分泌到粘液（不是血液或淋巴液）中，以及局部 IgG 提供针对阴道病毒挑战的强大保护。除了众所周知的抗体功能（例如， 中和作用、补体激活、调理作用），这是一个重要但很少被认可的效应功能 IgG的作用是捕获粘液中的病毒。 IgG与病毒表面结合可形成多重低亲和力粘合剂 病毒和粘液凝胶之​​间的交联。足够数量的这些低亲和力交联，可能 在亚中和 IgG 浓度下，可能会永久地将病毒捕获在粘液凝胶中。我们的飞行员 观察表明，极低浓度的特异性 IgGI 可以捕获 HSV-1 和病毒样病毒 否则会快速渗透粘液凝胶的颗粒。捕获减少了到达目标的病毒流量 细胞，并通过额外的保护机制促进失活和清除。将病毒困在 在病毒到达目标细胞之前产生粘液可能对于防御病毒至关重要，病毒一旦建立， 导致无法治愈的感染。最具保护性的抗体很可能不仅是中和抗体 通过阻止病毒进入靶细胞来捕获病毒颗粒，而且在捕获粘液中的病毒颗粒方面也非常有效。这 粘液中潜在的 IgG 捕获功能基本上未被认识到，因为大多数 IgG 活性研究 尚未在粘液盖斯中进行过。因此，迄今为止开发的所有单克隆抗体（MAb） 开发时没有考虑粘液中的这种免疫功能。