DataSheet_1_Cooperation Between Systemic IgG1 and Mucosal Dimeric IgA2 Monoclonal Anti-HIV Env Antibodies: Passive Immunization Protects Indian Rhesus Macaques Against Mucosal SHIV Challenges.docx

Understanding the interplay between systemic and mucosal anti-HIV antibodies can provide important insights to develop new prevention strategies. We used passive immunization via systemic and/or mucosal routes to establish cause-and-effect between well-characterized monoclonal antibodies and protection against intrarectal (i.r.) SHIV challenge. In a pilot study, for which we re-used animals previously exposed to SHIV but completely protected from viremia by different classes of anti-HIV neutralizing monoclonal antibodies (mAbs), we made a surprise finding: low-dose intravenous (i.v.) HGN194-IgG1, a human neutralizing mAb against the conserved V3-loop crown, was ineffective when given alone but protected 100% of animals when combined with i.r. applied HGN194-dIgA2 that by itself had only protected 17% of the animals. Here we sought to confirm the unexpected synergy between systemically administered IgG1 and mucosally applied dIgA HGN194 forms using six groups of naïve macaques (n=6/group). Animals received i.v. HGN194-IgG1 alone or combined with i.r.-administered dIgA forms; controls remained untreated. HGN194-IgG1 i.v. doses were given 24 hours before – and all i.r. dIgA doses 30 min before – i.r. exposure to a single high-dose of SHIV-1157ipEL-p. All controls became viremic. Among passively immunized animals, the combination of IgG1+dIgA2 again protected 100% of the animals. In contrast, single-agent i.v. IgG1 protected only one of six animals (17%) – consistent with our pilot data. IgG1 combined with dIgA1 or dIgA1+dIgA2 protected 83% (5/6) of the animals. The dIgA1+dIgA2 combination without the systemically administered dose of IgG1 protected 67% (4/6) of the macaques. We conclude that combining suboptimal antibody defenses at systemic and mucosal levels can yield synergy and completely prevent virus acquisition.

探究系统性及粘膜型抗HIV抗体的相互作用，可为开发新的预防策略提供重要洞见。本研究通过系统性及/或粘膜途径的被动免疫，建立了对已表征的单克隆抗体与抵抗直肠（i.r.）SHIV挑战之间的因果关系。在一项初步研究中，我们重新使用了先前接触过SHIV但完全通过不同类别的抗HIV中和单克隆抗体（mAbs）免于病毒血症的动物，并取得了令人惊奇的发现：低剂量静脉注射（i.v.）的HGN194-IgG1，作为一种针对保守的V3环冠的人源中和单克隆抗体，单独使用时无效，但与直肠应用HGN194-dIgA2结合时，后者本身仅保护了17%的动物，却能保护所有动物。本研究旨在通过使用六组未经免疫的猕猴（每组6只）来确认系统给予的IgG1与粘膜应用的dIgA HGN194形式之间意想不到的协同作用。动物单独接受i.v. HGN194-IgG1或与i.r.给予的dIgA形式结合；对照组未接受治疗。在给予SHIV-1157ipEL-p单次高剂量i.r.暴露前24小时给予HGN194-IgG1 i.v.剂量，所有i.r. dIgA剂量均在i.r.暴露前30分钟给予。所有对照组均出现病毒血症。在被动免疫的动物中，IgG1与dIgA2的结合再次保护了100%的动物。相比之下，单独使用i.v. IgG1仅保护了6只动物中的1只（17%），与我们的初步数据一致。IgG1与dIgA1或dIgA1与dIgA2的结合保护了83%（5/6）的动物。dIgA1与dIgA2的结合，在没有系统给予的IgG1剂量时，保护了67%（4/6）的猕猴。我们得出结论，将系统性及粘膜层的次优抗体防御相结合，可以产生协同效应，并完全预防病毒感染。