DEVELOPMENT OF A MONKEY MODEL FOR TESTING ANTIVIRAL AGENTS AGAINST HIV-1

开发用于测试抗 HIV-1 抗病毒药物的猴子模型

• 批准号: 6293725
• 负责人: Arifa S Khan
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6293725
• 关键词: AIDS therapy; AIDS vaccines; Macaca nemestrina; antibody titering; disease /disorder model; human immunodeficiency virus 1; longitudinal animal study; model design /development; neutralizing antibody; nonhuman therapy evaluation; recombinant virus; simian immunodeficiency virus; virus DNA; virus infection mechanism; virus replication

A good animal model for HIV-1 is essential for AIDS vaccine studies and development of efficacious anti-viral agents. Pig-tailed macaques have been found to be susceptible to HIV-1 infection (Agy, et al., 1992). Based upon this initial report, we previously infected 2 pig-tailed macaques (designated as PT86 and PT99) with HIV-1/LAI and have monitored long-term infection and clinical changes. Each animal responded uniquely to the infection. In the case of PT86 viral sequences (DNA and RNA) were detected in the PBMC in the first year whereas the lymph nodes were positive even at 3 years P.I. Antibodies to HIV-1 gag and env proteins have persisted in PT86. The CD4+/CD8+ ratio continues to gradually decline. In the case of PT99 viral DNA sequences were seen in the PBMCs upto 1 year and in the lymph node 3 years PI. Antibodies to the env proteins have persisted. No clinical symptoms have thusfar developed in PT86 or PT99. Since the clinical symptoms of AIDS in humans generally develop in 5-10 years and developed after about 10 years post-infection in one chimpanzee, it is most likely too early to see clinical symptoms in the infected pig-tailed macaques. The results thusfar indicate that HIV-1 infection of pig-tailed macaques may be similar to the infection seen in some humans: in the case of PT99 the infection is non-progressing whereas PT86 might represent a long-term survivor. Additional pig-tailed macaques have been infected with a preparation of HIV-1 produced in pig-tailed macaque PBMCs indicating reproducible infection of this species with a virus stock of HIV-1. To simulate the human situation where latent HIV-1 can be transiently stimulated with some vaccine injections, PT86, PT99 and other control animals were injected with tetanus toxoid without adjuvant. PBMCs were collected at the times points published for the human studies. The samples are currently being evaluated for virus isolation. HIV-1 DNA vaccine (CMV-DNA) produced persistent and boostable Gag and Env humoral repsonses in pig-tailed monkeys. The pig-tailed macaque model will be useful in evaluating protection by HIV-1 plasmid DNA vaccine against homologous challenge virus infection (HIV-1/LAI).

良好的 HIV-1 动物模型对于艾滋病疫苗研究和有效抗病毒药物的开发至关重要。已发现猪尾猕猴易受 HIV-1 感染（Agy 等，1992）。根据这份初步报告，我们之前用 HIV-1/LAI 感染了 2 只猪尾猕猴（指定为 PT86 和 PT99），并监测了长期感染和临床变化。 每只动物对感染都有独特的反应。在 PT86 的情况下，第一年在 PBMC 中检测到病毒序列（DNA 和 RNA），而淋巴结甚至在 3 年 P.I 时也呈阳性。 HIV-1 gag 和 env 蛋白的抗体在 PT86 中持续存在。 CD4+/CD8+比率继续逐渐下降。 就 PT99 而言，病毒 DNA 序列在 PBMC 中可观察到 1 年的病毒 DNA 序列，在淋巴结中可观察到 3 年的病毒 DNA 序列。针对 env 蛋白的抗体仍然存在。迄今为止，PT86 或 PT99 尚未出现临床症状。由于人类艾滋病的临床症状一般在5-10年内出现，而一只黑猩猩则在感染艾滋病后约10年出现，因此在受感染的猪尾猕猴中观察到临床症状很可能还为时过早。迄今为止的结果表明，猪尾猕猴的 HIV-1 感染可能与某些人类中看到的感染相似：在 PT99 的情况下，感染没有进展，而 PT86 可能代表长期幸存者。其他猪尾猕猴已被猪尾猕猴 PBMC 中产生的 HIV-1 制剂感染，表明该物种可重复感染 HIV-1 病毒库。 为了模拟人类通过注射某些疫苗可以暂时刺激潜伏的 HIV-1 的情况，PT86、PT99 和其他对照动物注射了不含佐剂的破伤风类毒素。在人类研究发布的时间点收集 PBMC。目前正在对样本进行病毒分离评估。 HIV-1 DNA 疫苗 (CMV-DNA) 在猪尾猴中产生持久且可增强的 Gag 和 Env 体液反应。猪尾猕猴模型将有助于评估 HIV-1 质粒 DNA 疫苗对同源攻击病毒感染 (HIV-1/LAI) 的保护作用。