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: 8515320
• 负责人: Samuel Lai
• 金额: $ 19.64万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8515320
• 关键词: Acquired Immunodeficiency Syndrome; Adhesives; Affinity; Antibodies; Binding; Blood; Cells; Complement; Complement Activation; Diffuse; Dose; Epithelial; Film; Gel; Genital system; HIV; Herpesvirus 1; Human; Immune; Immune system; Immunoglobulin G; Infection; Instruction; Lymph; Methods; Monoclonal Antibodies; Mucous body substance; Mus; Plantibodies; Plants; Safety; Seminal fluid; Simplexvirus; Surface; Testing; Vagina; Vaginal Ring; Viral; Virion; Virus; Virus-like particle; antibody-dependent cell cytotoxicity; base; cervicovaginal; crosslink; design; genital herpes; immune function; in vivo; microbicide; vaginal microbicide; vaginal transmission

PROJECT SUIVIMARY (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).

Suivimary项目（请参阅说明）： 对于阴道传播，病毒必须穿透粘液分泌才能到达靶细胞。我们最近发现，单纯疱疹病毒（HSV）和HIV很容易通过人宫颈阴道粘液扩散。免疫系统产生的大多数抗体（AB）分泌成粘液（不是血液或淋巴），而局部IgG可为阴道病毒挑战提供强大的保护。除了众所周知的抗体功能（例如中和，补体激活，调子化）外，IgG的重要效果功能是捕获粘液中的病毒。与病毒表面结合的IgG可能在病毒和粘液凝胶之​​间形成多个低亲和力的交联。这些低亲和力的十字链接数量可能在亚中和IgG浓度下，可能会永久将病毒捕获到粘液凝胶中。我们的试点观察结果表明，特定的IgGI浓度很低会捕获HSV-1和类似病毒的颗粒，这些颗粒否则会迅速穿透粘液凝胶。诱捕可减少到达靶细胞的病毒的通量，并通过其他保护机制促进失活和清除。在粘液到达靶细胞之前，将病毒捕获在粘液中可能是预防一旦建立引起无法治愈的感染的病毒至关重要的。最保护性抗体可能不仅是通过阻断病毒性进入靶细胞来中和病毒体的抗体，而且在粘液中捕获病毒体方面非常有效。粘液中这种潜在的IgG捕获功能在很大程度上未被认可，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）均未考虑粘液中这种免疫功能。在此提案中，我们试图鉴定植物生产的抗病毒IgG（PAB），以捕获人宫颈阴道粘液中的HSV和HIV，以及粘液和精液的混合物（AIM 1）。我们还将比较阴道环与薄膜传递的PAB的分布，以识别提供最低PAB剂量易感上皮表面的递送方法（AIM 2）。根据目标1和2，我们将测试在体内防止阴道HSV挑战的保护，并评估PABS和运输工具的安全性（AIM 3）。