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

感染和疾病的动物模型系统的开发， HIV-1对于艾滋病疫苗研究和干预至关重要。 目前， 唯一能被HIV-1感染的动物是黑猩猩; 但不会产生疾病。 由于维护成本巨大， 一只黑猩猩，事实上，这不可能是一个疾病模型， 模式被寻求。 根据一份来自华盛顿灵长类的报告 研究中心，进行了研究，以调查艾滋病毒-1感染 猪尾猴的实验 四只猴子接种了两种分离的 HIV-1的env区不同：两只被命名为PT 86的猴子 PT 99接受LAV，其env与实验室相似 适应株，HIV-1 IIIB;和两只猴，命名为PT 87和PT 89 接受了一种主要分离物（< 4代），其在其env中相似 MN菌株代表了北美大部分地区 HIV-1分离株。 只有PT 86和PT 99血清转化。 如果是PT 86， 增加的抗所有HIV-1蛋白的抗体滴度， 蛋白质印迹分析，在68周后仍然很高 接种（PI）。 在PI 6周时产生中和抗体。 从 在较早的测试时间点，从PBMC中分离感染性HIV-1， 4周PI。 PCR分析表明PBMCs在早期表达RNA 点（PI 4、6、8周），并在PI 40和52周再次进行。 84周时 PI，尽管PT 86在临床上保持健康，但在 可能存在CD 4/CD 8。在PT 99的情况下，仅针对env 检测到蛋白质;但是没有分离出病毒， CD 4/CD 8稳定。 这些结果表明，LAV感染， 在PT 86中复制，而迄今为止没有复制的证据。 在PT 99中看到。 研究正在进行中，以分析PT 87和PT 89的感染 被HIV-1病毒隔离为了在猴子中实现HIV-1疾病， 必须建立高水平持续病毒感染。 因此，在本发明中， 研究正在进行中，以分析各种宿主因素和病毒 导致HIV-1无法建立 猴子中持续的高水平感染。 一种方法是 构建了一种新的重组HIV-1 DNA，其中nef和LTR 基因已被致病性SIV分离株SIV 239取代。 这 一种被命名为SHIV-LTR的新型病毒已被证明能在猴子体内复制 比亲本HIV-1的效率更高。 研究正在 分析SHIV-LTR病毒的复制和致病潜力 在猴子身上。

The development of an animal model system for infection and disease by HIV-1 is essential for AIDS vaccine studies and intervention. Currently, the only animal species which can be infected by HIV-1 is the chimpanzee; however, no disease is produced. Due to the enormous cost of maintaining a chimpanzee and the fact that this cannot be a disease model, a better model was sought. Based upon a report from the Washington Primate Research Center, studies were undertaken to investigate HIV-1 infection in pig-tail monkeys. Four monkeys were inoculated with two isolates of HIV-1 which differ in their env regions: two monkeys designated as PT86 and PT99 received LAV, which is similar in its env to the laboratory adapted strain, HIV-1 IIIB; and two monkeys designated as PT87 and PT89 received a primary isolate (< 4 passages) which is similar in its env region to the MN strain, which represents the majority of North American HIV-1 isolates. Only PT86 and PT99 seroconverted. In case of PT86, an increasing antibody titer against all the HIV-1 proteins was seen by Western Blot analysis which has remained high at 68 weeks post inoculation (PI). Neutralizing antibodies developed at 6 weeks PI. From the early test time points, infectious HIV-1 was isolated from PBMCs at 4 weeks PI. PCR analysis of PBMCs indicated RNA expression at early time points (4, 6, 8 weeks PI) and again at 40 and 52 weeks PI. At 84 weeks PI, although PT86 has remained clinically healthy, a downward trend in CD4/CD8 may be occurring. In case of PT99, antibodies to only the env proteins were detected; however no virus has been isolated and the CD4/CD8 is stable. These results indicated that LAV infected and replicated in PT86 whereas no evidence of replication has thusfar been seen in PT99. Studies are underway to analyze infection of PT87 and PT89 by the primary HIV-1 isolate. To achieve HIV-1 disease in monkeys, a high level of persistent virus infection must be established. Thus, studies are in progress to analyze various host factors and viral determinants contributing towards the inability of HIV-1 to establish a persistent high level infection in monkeys. One approach has been construction of a novel recombinant HIV-1 DNA in which the nef and LTR genes have been substituted by SIV239, a pathogenic SIV isolate. This novel virus, designated as SHIV-LTR has proven to replicate in monkeys cells at a higher efficiency than the parent HIV-1. Studies are being performed to analyze replication and disease potential of SHIV-LTR virus in monkeys.