NONHUMAN PRIMATE MODELS FOR HIV VACCINE EVALUATION

生物医学研究的一个主要目标是开发一种能够 显著降低人类免疫缺陷新感染率 病毒(HIV)，不仅在这个国家，而且在世界范围内。虽然是积极的 结果来自非人类灵长类动物和人类阶段I和II 试验，两个案例都有明显的失败，强调 需要新的疫苗策略。基于这样一种假设，大多数 预防艾滋病毒感染和疾病的有效疫苗将是 不仅引起粘膜和全身的反应，而且引起体液和细胞的反应 广泛交叉反应的免疫反应，两种动物模型将 用于测试新疫苗和评估交叉反应免疫 来自同一分支或不同分支的HIV-1毒株。首先，希夫猕猴 模型将被用来表征系统和粘膜免疫反应 由嵌合的SIV/HIV病毒样颗粒和脊髓灰质炎病毒复制子引发 或者表达SIV和HIV抗原的裸露DNA疫苗。此外， 将尝试通过共同管理基因来增强这些反应 用候选疫苗编码各种细胞因子。免疫反应有待于 评估包括对血液和粘膜中抗体的诱导 分泌物，中和抗体活性，增殖反应 免疫原和细胞毒性T淋巴细胞活性。将对疗效进行评估 通过静脉或阴道向免疫猕猴发起挑战 致病性SHV-89.6P；然后将对这些动物进行监测以寻找证据 感染的可能性。第二，感染了来自分支的HIV-1毒株的黑猩猩 B、D或E将暴露在不相关的菌株中，定性和 正在进行的体液和细胞免疫反应的数量变化将 要下定决心。是否发生双重感染将通过聚合酶链式反应进行评估 前病毒DNA扩增、异源双链分析和DNA序列测定 分析。此外，幼年黑猩猩接种沙门氏菌后的病程 静脉、宫颈或直肠途径感染致病性HIV-1将是 与感染HIV-1的黑猩猩的特征和比较 接种了这种菌株后可能会发生双重感染。这些 研究将提供有关使用脊髓灰质炎病毒的可行性的信息 复制体和DNA疫苗引发保护性免疫反应，无论是 特定的细胞因子可以增强或改变所激发的免疫类型， 以及让黑猩猩接触多种HIV-1毒株是否成功 扩大交叉反应，从而预防感染或疾病。

A major goal of biomedical research is development of a vaccine that will lower significantly the rate of new infections of human immunodeficiency viruses (HIV), not only in this country, but worldwide. While positive results have come from both non-human primate and human Phase I and II trials, there have been obvious failures in both cases, emphasizing the need for novel vaccine strategies. Based on the hypothesis that the most effective vaccine against HIV infection and disease will be one that elicits not only mucosal and systemic but also humoral and cell-mediated immune responses that are broadly cross-reactive, two animal models will be used to test novel vaccines and assess cross-reactive immunity against HIV-1 strains from the same or different clades. First, the SHIV-macaque model will be used to characterize systemic and mucosal immune responses elicited by chimeric SIV/HIV virus-like particles and poliovirus replicons or naked DNA vaccines expressing SIV and HIV antigens. Furthermore, attempts will be made to enhance these responses by co-administering genes encoding various cytokines with candidate vaccines. Immune responses to be evaluated include inductions of antibodies in blood and mucosal secretions, neutralizing antibody activity, proliferative responses to immunogens, and cytotoxic T lymphocyte activity. Efficacy will be assessed by challenging immunized macaques either intravenously or vaginally with pathogenic SHIV-89.6P; these animals will then be monitored for evidence of infection. Second, chimpanzees infected with HIV-1 strains from clades B, D, or E will be exposed to unrelated strains, and both qualitative and quantitative changes in ongoing humoral and cellular immune responses will be determined. Whether super-infection occurs will be evaluated by PCR amplification of proviral DNA, heteroduplex assays, and DNA sequence analysis. In addition, disease course in naive chimpanzees inoculated by intravenous, cervical or rectal routes with a pathogenetic HIV-1 will be characterized and compared to that in HIV-1 infected chimpanzees which might become super-infected after inoculation with this strain. These studies will provide information on the feasibility of using poliovirus replicons and DNA vaccines to elicit protective immune responses, whether specific cytokines can enhance or alter the types of immunity elicited, and whether exposure of chimpanzees to multiple HIV-1 strains succeeds in broadening cross-reactivity such that infection or disease is prevented.