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， 大大降低新感染人体免疫机能丧失病毒的比率 艾滋病毒（HIV），不仅在这个国家，而且在全世界。而正 结果来自非人类灵长类动物和人类I期和II期 审判，在这两种情况下都有明显的失败，强调 需要新的疫苗策略。基于这样的假设， 针对艾滋病毒感染和疾病有效疫苗将是一种， 不仅粘膜和全身，而且体液和细胞介导 广泛交叉反应的免疫应答，两种动物模型将 用于测试新型疫苗和评估交叉反应性免疫， 来自相同或不同进化枝的HIV-1毒株。第一，SHIV猕猴 模型将用于表征全身和粘膜免疫应答 由嵌合SIV/HIV病毒样颗粒和脊髓灰质炎病毒复制子引起 或表达SIV和HIV抗原的裸DNA疫苗。此外，委员会认为， 将尝试通过共同施用基因来增强这些反应， 编码各种细胞因子的候选疫苗。免疫反应是 评估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。有效性评估期 通过静脉内或阴道内攻击免疫的猕猴， 致病性SHIV-89.6P;然后将监测这些动物的证据 感染其次，黑猩猩感染了来自分支的HIV-1毒株 B、D或E将暴露于无关菌株，定性和 正在进行的体液和细胞免疫应答的定量变化将 被确定。是否发生重复感染将通过PCR进行评估 原病毒DNA扩增、异源双链体测定和DNA测序 分析.此外，在未接种疫苗的黑猩猩中， 静脉、宫颈或直肠途径感染致病性HIV-1的患者将被 并与感染HIV-1的黑猩猩进行了比较， 在接种这种病毒后可能会被超级感染。这些 研究将提供关于使用脊髓灰质炎病毒的可行性的信息 复制子和DNA疫苗引发保护性免疫反应， 特异性细胞因子可增强或改变所引发的免疫类型， 以及黑猩猩接触多种HIV-1病毒株是否能成功地 扩大交叉反应性，从而预防感染或疾病。