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

良好的HIV-1动物模型对于艾滋病疫苗的研究和有效抗病毒药物的开发是至关重要的。已发现猪尾猕猴对HIV-1感染敏感(Agy等人，1992)。根据这份初步报告，我们先前感染了2只猪尾猕猴(编号为PT86和PT99)，感染了HIV-1/LAI，并监测了长期感染情况和临床变化。每种动物对感染的反应都是独特的。在PT86的病例中，第一年在PBMC中检测到病毒序列(DNA和RNA)，而即使在3年后淋巴结也呈阳性，抗HIV-1 Gag和env蛋白的抗体在PT86中持续存在。CD4+/CD8+比值继续呈逐渐下降趋势。在PT99病例中，病毒DNA序列在PBMC中持续1年，在淋巴结中持续3年。针对env蛋白的抗体一直存在。到目前为止，PT86或PT99没有出现临床症状。由于人类艾滋病的临床症状一般在5-10年内发展，在一只黑猩猩感染后大约10年后出现，因此现在就在受感染的猪尾猕猴身上看到临床症状很可能还为时过早。到目前为止的结果表明，猪尾猕猴感染HIV-1可能与一些人类的感染相似：在PT99的情况下，感染是无进展的，而PT86可能代表着一种长期的幸存者。更多的猪尾猕猴感染了由猪尾猕猴PBMC产生的HIV-1制剂，这表明该物种可复制感染HIV-1病毒。为了模拟一些疫苗注射可以短暂刺激潜伏的HIV-1的人类情况，PT86、PT99和其他对照动物被注射了无佐剂的破伤风类毒素。PBMC是在人体研究发表的时间点收集的。目前正在对样本进行病毒分离评估。HIV-1 DNA疫苗(CMV-DNA)在猪尾猴体内产生持久的、可增强的Gag和Env体液应答。猪尾猕猴模型可用于评价HIV-1质粒DNA疫苗对同源挑战病毒感染(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).