CHIMPANZEE/HIV MODEL FOR MUCOSAL CHALLENGE

艾滋病毒新感染病例继续上升， 其中大多数是性传播。 部分地区 艾滋病毒感染率的上升表明， 最终结果--发展为艾滋病--将继续是一个主要的健康问题， 威胁 因为改变人类的性行为和行为是不现实的， 目标，减少传播的最有效方法是防止新的 预防性接种的感染。 因此，这一长期目标 一项提议是研制一种有效的艾滋病疫苗。 以来 大多数新感染是在接触分泌物后获得的 在性行为中或使用受污染的针头进行静脉注射时 一个成功的疫苗必须引起全身性的， 和粘膜免疫。 测试各种抗原的最直接方法， 用于最佳诱导免疫应答的抗原递送系统， 是在动物模型中。 因为唯一的动物 该模型再现了人类艾滋病毒的自然史，尽管没有 进展到艾滋病，是艾滋病毒感染的黑猩猩，这个模型将是 用于（i）开发通过暴露粘膜感染的可靠方法 （ii）定义粘膜和全身体液和细胞- 由粘膜感染诱导的介导的免疫应答;和（iii）使用 由此产生的信息，以测试艾滋病毒特异性免疫的能力， 候选疫苗引起的反应，以预防以下感染 粘膜或肠胃外接种HIV。 具体而言，建议 研究包括使用无细胞和细胞相关的HIV感染 黑猩猩的直肠粘膜或尿道管暴露于 病毒 针对这些传播途径的可靠方法将补充 一个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。 粘液和全身体液和细胞- 介导的HIV特异性免疫应答， 粘膜途径将与 静脉注射 这些结果将构成以下方面的基础： 评估HIV免疫原的效力及其引发 （推定的）保护性免疫反应。 最后，候选艾滋病毒疫苗， 模仿成功预防粘膜感染的疫苗 SIV-猕猴模型，将在黑猩猩中测试免疫原性， 将相对于HIV感染黑猩猩的反应进行评估， 对于保护功效，将通过粘膜和 免疫动物胃肠外暴露于感染性HIV。 这些研究 应提供关于发展的可行性的宝贵信息 可诱导粘膜和全身免疫应答的疫苗 能够预防HIV的粘膜和肠胃外感染。

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.