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)，而即使在感染后3年，淋巴结中也是阳性的。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HIV-1 Gag和env蛋白的抗体在PT86中持续存在，而在PT99中仅看到并持续存在针对env蛋白的抗体。在感染后3年，PT 86和PT 99的Env滴度高于感染后6年。虽然PT86的CD4+/CD8+比值逐渐下降，并维持在较低水平，但PT86或PT99迄今未出现临床症状。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。另一只猪尾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，以确定感染动物的病毒载量，以进一步评估猪尾猕猴的HIV-1感染情况，以此作为人类长期无进展的模型。为分析潜伏的HIV-1的激活情况，给PT86、PT99等对照动物注射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。未见病毒诱导。然而，在另一项评估破伤风类毒素效力的研究中，也发现在没有佐剂的情况下，对破伤风类毒素的抗体应答比在有佐剂的类毒素的情况下要低。这些动物将被注射有效的破伤风类毒素，以进一步分析感染猪尾猴的HIV-1活性。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。用同源病毒(HIV-1/LAI)攻击DNA免疫的猪尾猕猴。目前正在研究评估DNA疫苗在感染HIV-1的猪尾猕猴模型中的效果。

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.