PASSIVE ANTIBODY PROTECTION IN SHIV CHALLENGE MODEL

描述 (改编自申请人的摘要)被动地管理特定的 抗体可以预防脊髓灰质炎等病毒引起的疾病， 麻疹、风疹、水痘、甲型肝炎和乙肝，而抗体 研究人员推测，单独使用可能不能预防HIV-1感染 在系统和粘膜间隔中预先存在的抗体可能是一种 预防艾滋病毒-1传播的重要组成部分。匮乏 一种易于支持复制HIV-1的动物挑战模型 初步分离和模拟性感染艾滋病毒的生理学 使得进行被动迁移研究变得困难，这将澄清 体液与保护相关。另一个障碍是很少有人 可用的抗体似乎能够有效地中和原发 HIV-1分离株。调查人员最近证明了三个 抗体试剂(多克隆HIVIG和人源单抗2F5和2G12) 中和HIV-1主要毒株，共同发挥协同作用 中和活性。他们建议研究被动运动的功效。 给予这些抗体(单独或联合使用)预防 新城疫病毒感染猕猴的初步研究 分离株(SIV-89.6)。实验将包括静脉注射和阴道内注射 挑战，体内保护将与测量的 血清和粘膜中HIV特异性抗体。我们将特别强调 作为性传播模式的阴道内激发系统的研究 HIV-1。其主要目的是评估 被动转移抗体与体液免疫的认识 保护的关联性。此外，由于生殖道树突状细胞 很可能是HIV-1感染的最初目标，调查人员将 使用皮肤和血液来源的树突状细胞进行中和抗体检测 作为HIV-1感染目标的细胞。 具体目标1.建立能够检测抗体介导的体外检测方法 用人树突状细胞中和血清和肌肉标本中的病毒 作为HIV-1感染目标的细胞。 特定目的2.评价被动给药的体内疗效 抗HIV-1抗体组合对恒河猴免疫保护作用的研究 静脉注射和肌肉注射SIV挑战。 特定目标3.体内对SIV攻击的保护与血清的相关性 和肌肉抗体水平。

DESCRIPTION (Adapted from the applicant's abstract) Passive administration of specific antibody can protect against disease caused by viruses such as polio, measles, rubella, varicella, hepatitis A and hepatitis B. While antibody alone may not protect against HIV-1 infection, the investigators hypothesize that pre-existing antibody in systemic and mucosal compartments may be an important component of protection against transmission of HIV-1. The lack of an animal challenge model for HIV-1 that readily supports replication of primary isolates and simulates the physiology of sexual HIV-infection has made it difficult to perform passive transfer studies that would elucidate humoral correlates of protection. An additional obstacle is that few available antibodies appear capable of potent neutralization of primary HIV-1 isolates. The investigators have recently demonstrated that three antibody reagents (a polyclonal HIVIG and human Mabs 2F5 and 2G12) each neutralize primary HIV-1 strains and together, display synergistic neutralizing activity. They propose to study the efficacy of passive administration of these antibodies (alone or in combination) in preventing macaque infection by a SHIV containing the HIV-1 envelope of a primary isolate (SHIV-89.6). Experiments will include intravenous and intravaginal challenge, and in-vivo protection will be correlated to measured levels of serum and mucosal HIV-specific antibody. Particular emphasis will be placed on the intravaginal challenge system as a model of sexual transmission of HIV-1. The main objectives are to evaluate the protective efficacy of passively transferred antibody and to understand the humoral immune correlates of protection. In addition, since genital tract dendritic cells are likely initial targets of HIV-1 infection, the investigators will perform neutralizing antibody assays using skin and blood derived dendritic cells as targets of HIV-1 infection. Specific Aim 1. Develop in-vitro assays that can measure antibody-mediated virus neutralization from serum and muscosal specimens using human dendritic cells as targets of HIV-1 infection. Specific Aim 2. Evaluate the in-vivo efficacy of passive administration of anti-HIV-1 antibody combinations in protection of rhesus macaques against intravenous and muscosal SHIV challenge. Specific Aim 3. Correlate in-vivo protection from SHIV challenge with serum and muscosal antibody levels.