Optimizing Plantibodies for Trapping HIV and HSV in Cervicovaginal Mucus

优化 Plantibodies 以捕获宫颈阴道粘液中的 HIV 和 HSV

• 批准号: 8900905
• 负责人: Samuel Lai
• 金额: $ 15.93万
• 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 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8900905
• 关键词: Acquired Immunodeficiency Syndrome; Adhesives; Affinity; Animals; Antibodies; Binding; Biological Assay; Blood; Cells; Clinical; Complement; Complement Activation; Diffuse; Dose; Drug Formulations; Epithelial; Epithelium; Epitopes; Failure; Fiber; Film; Frequencies; Gel; Genital system; HIV; Herpesvirus 1; Human; Image; Immune; Immune system; Immunoglobulin A; Immunoglobulin G; In Vitro; Infection; Infection prevention; Instruction; Label; Lymph; Macaca; Measures; Methods; Modeling; Monoclonal Antibodies; Mucins; Mucous body substance; Mus; Pattern; Plantibodies; Plants; Predisposition; Prevention; Regimen; Research Personnel; Safety; Secretory Immunoglobulin A; Seminal Plasma; Seminal fluid; Simplexvirus; Surface; Testing; Time; Toxic effect; Vagina; Vaginal Ring; Vaginal delivery procedure; Viral; Virion; Virus; Virus Diseases; Virus-like particle; Work; base; cervicovaginal; crosslink; design; experience; genital herpes; glycosylation; immune function; in vivo; macrophage; microbicide; neutralizing monoclonal antibodies; next generation; particle; pathogen; polymeric IgA; prevent; vaginal microbicide; vaginal transmission; vector

PROJECT SUMMARY (See Instructions): For vaginal transmission, viruses must penetrate mucus secretions to reach target cells; we recently 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. In this proposal, we seek to identify themost potent plant-produced anti-viral IgGs (PAbs) for trapping HSV and HIV in human cervicovaginal mucus as well as in mixtures of mucus and semen (Aim 1). We will also compare the distribution of PAbs delivered by vaginal ring vs. film to identify the delivery method that provides complete coverage of susceptible epithelial surface at the lowest PAb dose (Aim 2). Based on Aims 1 & 2, we will test for protection against vaginal HSV challenge in vivo, as well as evaluate the safety of the PAbs and delivery vehicle (Aim 3).

项目摘要（参见说明）： 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。免疫系统产生的大多数抗体 (Ab) 都会分泌到粘液（而不是血液或淋巴液）中，局部 IgG 可提供针对阴道病毒攻击的强大保护。除了众所周知的抗体功能（例如中和、补体激活、调理作用）之外，IgG 的一个重要但鲜为人知的效应功能是捕获粘液中的病毒。与病毒表面结合的 IgG 可以在病毒和粘液凝胶之​​间形成多个低亲和力的粘合交联。足够数量的低亲和力交联，可能在亚中和 IgG 浓度下，可以将病毒永久捕获在粘液凝胶中。我们的初步观察表明，极低浓度的特异性 IgGI 可以捕获 HSV-1 和病毒样颗粒，否则它们会迅速渗透粘液凝胶。捕获减少了到达靶细胞的病毒流量，并通过额外的保护机制促进灭活和清除。在病毒到达目标细胞之前将其捕获在粘液中可能对于预防病毒至关重要，这些病毒一旦建立就会导致无法治愈的感染。最具保护性的抗体很可能是那些不仅可以通过阻止病毒进入靶细胞来中和病毒粒子，而且可以非常有效地将病毒粒子捕获在粘液中的抗体。粘液中这种潜在的 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中进行。因此，迄今为止开发的所有单克隆抗体（MAb）都没有考虑粘液中的这种免疫功能。在本提案中，我们寻求鉴定最有效的植物产生的抗病毒 IgG (PAb)，用于捕获人类宫颈阴道粘液以及粘液和精液混合物中的 HSV 和 HIV（目标 1）。我们还将比较阴道环与薄膜递送的 PAb 分布，以确定以最低 PAb 剂量完全覆盖易感上皮表面的递送方法（目标 2）。基于目标 1 和 2，我们将测试体内针对阴道 HSV 攻击的保护作用，并评估 PAb 和运载工具的安全性（目标 3）。