CHIMPANZEE/HIV MODEL FOR MUCOSAL CHALLENGE

黑猩猩/HIV 粘膜挑战模型

• 批准号: 3747023
• 负责人: PATRICIA N FULTZ
• 金额: --
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3747023
• 关键词: AIDS vaccines; Pan; cell free system; cellular immunity; cervix; disease /disorder model; enzyme linked immunosorbent assay; human immunodeficiency virus 1; humoral immunity; immunization; mucosa; neutralizing antibody; nonhuman therapy evaluation; secretory immune system; vagina; virus antigen

The incidence of new infections of HIV continues to rise, with the majority of these resulting from sexual transmission. In some areas of the world, the rate of increase indicates that HIV infection and its ultimate outcome--progression to AIDS--will continue to be a major health threat. Since changing human sexuality and behavior is an unrealistic goal, the most efficient way to decrease transmission is to prevent new infections by prophylactic vaccination. Thus, the long-term goal of this proposal is to develop an efficacious vaccine against HIV. Since the majority of new infections are acquired after exposure to secretions during sex or to blood while using contaminated needles for intravenous administration of drugs, a successful vaccine must elicit both systemic and mucosal immunity. The most direct way to test various antigens and antigen-delivery systems for optimum induction of an immune response and for protective efficacy is in an animal model. Since the only animal model that reproduces the natural history of HIV in humans, albeit without progression to AIDS, is HIV infection of chimpanzees, this model will be used (i) to develop reliable methods for infection by exposure of mucosal surfaces to HIV; (ii) to define mucosal and systemic humoral and cell- mediated immune responses induced by mucosal infection; and (iii) to use the resulting information to test the ability of HIV-specific immune responses elicited by candidate vaccines to prevent infection following mucosal or parenteral inoculation of HIV. Specifically, the proposed studies include the use of cell-free and cell-associated HIV to infect chimpanzees by exposure of the rectal mucosa or urethral canal to the virus. Reliable methods for these routes of transmission will complement an already established model of HIV infection of female chimpanzees via the cervical/vaginal mucosa. Mucosal and systemic humoral and cell- mediated HIV-specific immune responses induced as a result of infection by mucosal routes will be compared with responses that develop after intravenous inoculation. These results will form the basis on which to assess the potency of HIV immunogen(s) and their ability to elicit (putative) protective immune responses. Lastly, candidate HIV vaccines, modeled after vaccines that successfully prevent mucosal infections in the SIV-macaque model, will be tested in chimpanzees for immunogenicity, which will be evaluated relative to responses in HIV-infected chimpanzees, and for protective efficacy, to be tested in parallel by mucosal and parenteral exposure of immunized animals to infectious HIV. These studies should provide valuable information on the feasibility of developing vaccines that can induce both mucosal and systemic immune responses capable of preventing mucosal and parenteral infection by HIV.

艾滋病毒新发感染者的发病率持续上升， 其中大部分是由性传播引起的。 在某些地区 世界范围内，增长率表明艾滋病毒感染及其 最终结果——进展为艾滋病——将继续成为一个主要的健康问题 威胁。 由于改变人类的性取向和行为是不现实的 目标，减少传播的最有效方法是防止新的传播 通过预防性疫苗接种感染。 因此，本次活动的长期目标是 提案是开发一种有效的艾滋病毒疫苗。 自从 大多数新感染是在接触分泌物后获得的 性行为期间或使用受污染的针头进行静脉注射时接触血液 药物管理，成功的疫苗必须引起系统性 和粘膜免疫。 最直接的方法来检测各种抗原和 用于最佳诱导免疫反应的抗原递送系统和 保护功效是在动物模型中进行的。 由于是唯一的动物 重现人类艾滋病毒自然史的模型，尽管没有 进展为艾滋病，是黑猩猩感染艾滋病毒，这个模型将是 用于 (i) 开发通过暴露粘膜进行感染的可靠方法 表面有艾滋病毒； (ii) 定义粘膜和全身体液和细胞- 粘膜感染诱导的介导免疫反应； (iii) 使用 所得信息可测试 HIV 特异性免疫能力 候选疫苗引起的反应以预防感染 HIV的粘膜或胃肠外接种。 具体来说，拟议的 研究包括使用无细胞和细胞相关的艾滋病毒来感染 黑猩猩通过将直肠粘膜或尿道暴露于 病毒。 这些传播途径的可靠方法将起到补充作用 已经建立的雌性黑猩猩艾滋病毒感染模型 宫颈/阴道粘膜。 粘膜和全身体液和细胞 介导的 HIV 特异性免疫反应是由感染引起的 粘膜途径将与之后产生的反应进行比较 静脉注射。 这些结果将构成基础 评估 HIV 免疫原的效力及其引发的能力 （假定的）保护性免疫反应。 最后，候选艾滋病毒疫苗， 以成功预防粘膜感染的疫苗为模型 SIV-猕猴模型将在黑猩猩中进行免疫原性测试， 将根据感染艾滋病毒的黑猩猩的反应进行评估，并且 保护功效，通过粘膜和 免疫动物肠外暴露于传染性艾滋病毒。 这些研究 应提供关于开发可行性的有价值的信息 可以诱导粘膜和全身免疫反应的疫苗 能够预防艾滋病毒的粘膜和肠外感染。