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

良好的HIV-1动物模型对艾滋病疫苗研究和有效抗病毒药物的开发至关重要。已发现长尾猕猴易感染HIV-1 （Agy等，1992）。基于这一初步报告，我们之前感染了2只长尾猕猴（命名为PT86和PT99） HIV-1/LAI，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病例中，第一年在PBMC中检测到PT86病毒序列（DNA和RNA），而淋巴结甚至在3岁时也呈阳性。HIV-1 gag和env蛋白抗体在PT86中持续存在。CD4+/CD8+比值继续逐渐下降。PT99病毒DNA序列在1年的pbmc和3年的淋巴结中可见。针对env蛋白的抗体一直存在。迄今为止，PT86或PT99未出现临床症状。由于人类艾滋病的临床症状通常在5-10年内出现，而在一只黑猩猩感染后约10年后出现，因此在被感染的长尾猕猴身上看到临床症状很可能还为时过早。到目前为止，研究结果表明，长尾猕猴的HIV-1感染可能与某些人类的感染相似：在PT99的情况下，感染没有进展，而PT86可能代表长期存活。已经有更多的长尾猕猴感染了在长尾猕猴pbmc中产生的HIV-1制剂，这表明该物种被HIV-1病毒库可重复感染。为了模拟人类潜伏性HIV-1可以被某些疫苗短暂刺激的情况，我们给PT86、PT99等对照动物注射了不加佐剂的破伤风类毒素。pbmc是在发表人类研究的时间点收集的。目前正在对这些样本进行病毒分离评估。HIV-1 DNA疫苗（CMV-DNA）在长尾猴中产生持久和可促进的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。

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).