CHIMPANZEE/HIV MODEL FOR MUCOSAL CHALLENGE

新感染艾滋病毒的人数继续上升， 其中大部分是由性传播引起的。在一些地区 在世界范围内，增长的速度表明艾滋病毒感染及其 最终结果--发展为艾滋病--仍将是一个主要的健康问题 威胁。因为改变人类的性取向和行为是不切实际的 目标，减少传播的最有效方法是防止新的 预防性接种引起的感染。因此，这一计划的长期目标是 建议是开发一种有效的艾滋病毒疫苗。自.以来 大多数新感染是在接触分泌物后获得的 在性行为中或在使用受污染的针头静脉注射时接触血液 给药，一个成功的疫苗必须引起 和粘膜免疫力。检测各种抗原的最直接方法 用于最佳诱导免疫反应的抗原递送系统和 保护效果是在动物模型中进行的。因为唯一的动物 在人类体内复制艾滋病毒自然历史的模型，尽管没有 进展为艾滋病，是感染艾滋病毒的黑猩猩，这个模型将 用于(I)开发通过暴露粘膜感染的可靠方法 艾滋病毒的表面；(Ii)定义粘膜和全身体液和细胞- 粘膜感染诱导的介导性免疫反应；和(Iii)使用 由此得到的信息可以测试HIV特异性免疫的能力 候选疫苗引起的预防以下感染的反应 通过粘膜或非肠道接种艾滋病毒。具体地说，建议的 研究包括使用无细胞和细胞相关的艾滋病毒来感染 黑猩猩将直肠粘膜或尿道口暴露在 病毒。这些传播途径的可靠方法将是补充 已经建立的雌性黑猩猩感染艾滋病毒的模型 宫颈/阴道粘膜。粘膜和全身体液和细胞- 感染引起的介导的HIV特异性免疫反应 粘膜途径将与之后发展的反应进行比较。 静脉接种。这些结果将形成以下基础 评估艾滋病毒免疫原的效力(S)及其诱导能力 (假定)保护性免疫反应。最后，候选艾滋病毒疫苗， 仿照成功预防肠道粘膜感染的疫苗 SIV-猕猴模型，将在黑猩猩身上测试免疫原性，这 将相对于感染艾滋病毒的黑猩猩的反应进行评估，以及 对于保护效果，将由粘膜和 免疫动物的肠道外暴露于传染性艾滋病毒。这些研究 应提供有关开发的可行性的有价值的信息 既能诱导粘膜免疫反应又能诱导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。

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.