NONHUMAN PRIMATE MODELS FOR HIV VACCINE EVALUATION

用于艾滋病毒疫苗评估的非人类灵长类动物模型

• 批准号: 6338604
• 负责人: Patricia N Fultz
• 金额: $ 26.83万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6338604
• 关键词: AIDS vaccines; Macaca mulatta; Pan; Primates; attenuated microorganism; cell free system; cellular immunity; cervix; cytokine; disease /disorder model; enzyme linked immunosorbent assay; genetic strain; human immunodeficiency virus 1; humoral immunity; immunization; model design /development; mucosal immunity; nonhuman therapy evaluation; poliovirus; provirus; replicon; simian immunodeficiency virus; vagina; virus antigen

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.

生物医学研究的一个主要目标是开发一种疫苗 显着降低人类免疫缺陷的新感染率 病毒（艾滋病毒），不仅在这个国家，而且在全世界。积极的同时 结果来自非人类灵长类动物和人类 I 期和 II 期 试验中，这两个案例都出现了明显的失败，强调 需要新的疫苗策略。基于以下假设：最 针对艾滋病毒感染和疾病的有效疫苗将是一种 不仅引起粘膜和全身性的，而且还引起体液和细胞介导的 免疫反应广泛交叉反应，两种动物模型将 用于测试新型疫苗并评估交叉反应免疫力 来自相同或不同进化枝的 HIV-1 毒株。首先，SHIV-猕猴 模型将用于表征系统和粘膜免疫反应 由嵌合 SIV/HIV 病毒样颗粒和脊髓灰质炎病毒复制子引发 或表达 SIV 和 HIV 抗原的裸 DNA 疫苗。此外， 将尝试通过共同施用基因来增强这些反应 与候选疫苗一起编码各种细胞因子。免疫反应应 评估的包括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。将评估功效 通过静脉注射或阴道注射来挑战已免疫的猕猴 致病性 SHIV-89.6P；然后将监测这些动物以获取证据 的感染。其次，黑猩猩感染了来自进化枝的 HIV-1 病毒株 B、D 或 E 将暴露于不相关的菌株，并且定性和 持续的体液和细胞免疫反应的数量变化将 被确定。是否发生重复感染将通过PCR评估 原病毒 DNA 扩增、异源双链分析和 DNA 序列 分析。此外，幼稚黑猩猩的疾病过程 带有致病性 HIV-1 的静脉内、宫颈或直肠途径将被 特征并与感染 HIV-1 的黑猩猩进行比较 接种该菌株后可能会出现超级感染。这些 研究将提供有关使用脊髓灰质炎病毒可行性的信息 复制子和DNA疫苗来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引发的免疫类型， 以及让黑猩猩接触多种 HIV-1 病毒株是否能成功 扩大交叉反应性，从而预防感染或疾病。