PASSIVE ANTIBODY PROTECTION IN SHIV CHALLENGE MODEL

SHIV 挑战模型中的被动抗体保护

• 批准号: 6056489
• 负责人: John R Mascola
• 金额: $ 34.43万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6056489
• 关键词: Macaca mulatta; antiviral antibody; dendritic cells; disease /disorder model; human immunodeficiency virus 1; humoral immunity; intravenous administration; monoclonal antibody; mucosa; mucosal immunity; neutralizing antibody; passive immunization; sexually transmitted diseases; simian immunodeficiency virus; vagina

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.

描述 （根据申请人摘要改编） 抗体可以预防由病毒引起的疾病，如脊髓灰质炎， 麻疹、风疹、水痘、甲肝和B。而抗体 研究人员推测， 在全身和粘膜隔室中预先存在的抗体可能是 预防HIV-1传播的重要组成部分。 缺乏 HIV-1的动物攻击模型很容易支持复制， 初级隔离和模拟性HIV感染的生理学， 很难进行被动转移研究， 保护的体液相关物。 另一个障碍是， 可用的抗体似乎能够有效中和原发性 HIV-1分离株。 调查人员最近证实， 抗体试剂（多克隆HIVIG和人Mab 2F 5和2G 12）各自 中和主要HIV-1菌株， 中和活性 他们建议研究被动的 施用这些抗体（单独或组合）以预防 猕猴感染含有HIV-1包膜的SHIV病毒， 分离株（SHIV-89.6）。 实验将包括静脉注射和阴道内 攻击和体内保护将与测量的 血清和粘膜HIV特异性抗体。 将特别强调 阴道内挑战系统作为性传播的模型， HIV-1 主要目的是评价 被动转移抗体，了解体液免疫 保护的相关性。 此外，由于生殖道树突细胞 可能是HIV-1感染的最初目标，研究人员将 使用皮肤和血液衍生的树突状细胞进行中和抗体测定 细胞作为HIV-1感染的目标。 具体目标1. 开发可以测量抗体介导的 使用人树突状细胞从血清和粘膜样品中中和病毒 细胞作为HIV-1感染的目标。 具体目标2。 评价被动施用的体内功效 抗HIV-1抗体组合保护恒河猴免受 静脉注射和肌肉注射SHIV攻击。 具体目标3。 与血清对SHIV攻击的体内保护相关 和Muscosal抗体水平。