NOVEL VECTOR DESIGN TO EXPRESS MULTIPLE ANTIGENS

描述：（改编自申请人的摘要）开发一种安全， 有效和负担得起的HIV-1疫苗可能是最有效的 在全球范围内控制HIV-1感染。然而，基因和 HIV-1的生物学变异性是疫苗的重大障碍 发展最近的证据表明，CTL可能在清除 在原发性感染期间的病毒血症和维持无病状态 HIV-1感染者。因此，开发艾滋病毒疫苗的努力应该集中在 作为一个主要组成部分，诱导广泛的交叉反应性CTL应答。一 在体内产生有效CTL应答的有希望的方法是通过 使用DNA疫苗。使用HIV-1 env和gag/pol DNA的当前工作 作为免疫原的构建体表明需要额外的疫苗组分 给予广泛的保护。因此，一种假定的HIV-1疫苗 通过包括另外的免疫原性靶。除了结构 和酶蛋白，HIV-1还含有调节和辅助基因。 这些基因在体内是高度保守的，并且可以提供额外的靶点， CTL应答。我们假设这些靶点可以诱导广泛的 病毒特异性CTL反应，可以帮助限制病毒逃逸，并赋予 保护免受病毒攻击。使用辅助基因作为 多组分疫苗，我们已经设计了一种新的构建体， HIV-1辅助基因vif、vpu和nef受单个启动子控制。 为了测试“概念证明”，我们提出以下目标：（1）我们将 免疫人HLA-A2转基因小鼠及其细胞免疫评价 使用HIV-1感染的人类目标的反应;（2）我们将使用非人类 灵长类动物模型来测试这种疫苗构建体赋予 单独或与env和gag/pol疫苗联合使用提供保护 结构。我们假设，由细胞因子诱导的细胞介导的反应， 辅助基因可能包括对不同HIV-1进化枝的更广泛识别， 在预防性和治疗性疫苗接种中都是有用 艾滋病病毒1的预防计划。

DESCRIPTION: (Adapted from Applicant's Abstract) Development of a safe, effective and affordable vaccine for HIV-1 is potentially the most efficient means of controlling HIV-1 infection worldwide. However, the genetic and biological variability of HIV-1 represents significant obstacles for vaccine development. Recent evidence indicates that CTLs may play a role in clearing viremia during primary infection and maintaining a disease-free state in HIV-1-infected patients. Thus, efforts to develop an HIV vaccine should focus on eliciting a broad cross-reactive CTL response as one major component. One promising approach to generating an effective CTL response in vivo is through the use of DNA vaccination. Current efforts using HIV-1 env and gag/pol DNA constructs as immunogens suggest that additional vaccine components are needed to confer broad protection. Therefore, a putative HIV-1 vaccine might benefit by inclusion of additional immunogenic targets. In addition to the structural and enzymatic proteins, HIV-1 also contains regulatory and accessory genes. These genes are highly conserved in vivo and may provide additional targets for CTL responses. We hypothesize that such targets could induce a broad virus-specific CTL response that could help to limit viral escape and confer protection against viral challenge. To use the accessory genes as part of a multicomponent vaccine, we have engineered a novel construct that expresses HIV-1 accessory genes vif, vpu, and nef under the control of a single promoter. To test the "proof of concept" we propose the following aims: (1) We will immunize human HLA-A2 transgenic mouse and evaluate the cellular immune responses using HIV-1 infected human targets; (2) we will use a non-human primate model to test the ability of this vaccine construct to confer protection either alone or in combination with env and gag/pol vaccine constructs. We hypothesize that cell-mediated responses induced by the accessory genes may include broader recognition of divergent HIV-1 clades and should be useful in both prophylactic as well as therapeutic vaccination schemes against HIV-1.