Development of a monkey model for testing antiviral agents against HIV-1

开发用于测试 HIV-1 抗病毒药物的猴子模型

• 批准号: 6433509
• 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/6433509
• 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 post-infection. 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 HIV-1 gag and env proteins have persisted in PT86 where in PT99 only antibodies to the env proteins were seen and have persisted. Higher Env titers were seen in PT 86 and PT 99 at 3 years post-infection than at 6 years post-infection. Although the CD4+/CD8+ ratio gradually declined in PT 86 and was maintained at a lower level, 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. Another pig-tailed macaque was recently infected a lower dose of HIV-1 and developed antibodies to Gag and Env. Studies are currently underway to determine the viral load in the infected animals to further evaluate HIV-1 infection in pig-tailed macaques as a model for human long-term non-progressors. To analyze activation of latent HIV-1, 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. Virus induction was not seen. However, in another to evaluate tetanus toxoid potency, it was also found that the antibody response to tetanus toxoid without adjuvant was less than that seen in the case of toxoid with adjuvant. The animals will be injected with the potent tetanus toxoid to further analyze HIV-1 activation in infected pig-tailed monkeys. HIV-1 DNA vaccine (CMV-DNA) produced persistent and boostable Gag and Env humoral repsonses in pig-tailed monkeys. The DNA immunized pig-tailed macaques were challenged with homologous virus (HIV-1/LAI). Studies are underway to evaluate efficacy of the DNA vaccine in HIV-1 infected pig-tailed macaque model.

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。已发现猪尾猕猴容易感染 HIV-1（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。就 PT86 而言，第一年在 PBMC 中检测到病毒序列（DNA 和 RNA），而淋巴结甚至在感染后 3 年仍呈阳性。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 HIV-1 gag 和 env 蛋白的抗体在 PT86 中持续存在，而在 PT99 中仅观察到针对 env 蛋白的抗体并持续存在。感染后 3 年，PT 86 和 PT 99 的 Env 滴度高于感染后 6 年。尽管CD4+/CD8+比率在PT 86中逐渐下降并维持在较低水平，但在PT86或PT99中迄今尚未出现临床症状。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。另一只猪尾猕猴最近感染了较低剂量的 HIV-1，并产生了针对 Gag 和 Env 的抗体。目前正在进行研究以确定受感染动物的病毒载量，以进一步评估猪尾猕猴中的 HIV-1 感染情况，将其作为人类长期无进展者的模型。为了分析潜伏 HIV-1 的激活，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。未观察到病毒诱导。然而，在另一项评估破伤风类毒素效力的研究中，也发现对不含佐剂的破伤风类毒素的抗体反应低于对含有佐剂的类毒素的情况。这些动物将被注射强效破伤风类毒素，以进一步分析受感染猪尾猴体内 HIV-1 的激活情况。 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。 DNA免疫的猪尾猕猴受到同源病毒（HIV-1/LAI）的攻击。目前正在进行研究评估 DNA 疫苗在 HIV-1 感染的猪尾猕猴模型中的功效。