HIV/SIV STRUCTURAL GENE VECTORS AS A LIVE HIV VACCINE

描述（改编自申请人摘要）：成功的HIV 疫苗必须诱导保护性HIV特异性CTL应答。一个活生生的- 减毒艾滋病毒疫苗提供了一种有希望的策略，以提高艾滋病毒- 特异性CTL应答。HIV-I的遗传简单衍生物已经被 作为一种安全的减毒活HIV疫苗的新方法。 的 该项目是基于一个假设，即感染艾滋病毒 结构基因载体（SGV）提供保护性免疫， 感染不同种类的艾滋病毒。SGV是一种独特的逆转录病毒 表达由HIV组成的可复制病毒的载体 结构蛋白，但缺乏与发病机制相关的HIV基因。 由于其独特的遗传结构，SGV是Tat独立的 组成型复制HIV gag、pot、env和最小补体 附属基因的数量SGV的复制提供自然呈现 抗原呈递细胞中的HIV结构蛋白，这确保了 通过MHC I类分子对细胞介导免疫的最佳刺激， II类介绍。有限的复制周期产生遗传 对于诱导针对不同菌株的免疫力重要的变异 但最大限度地减少有害插入或重组的机会 活动HIV SGV基于原型牛白血病病毒（BLV） SGV在两种BLV中具有传染性、免疫原性和缺乏致病性 动物模型本研究的总体目标是检验这一假设 SGV在替代SIV猴中具有传染性和免疫原性 艾滋病和B细胞淋巴瘤的模型。 具体目标是：（1）确定 HIV辅助基因的最小组合， HIV SGV在培养细胞和原代细胞中的复制; 2）开发 类似SIV SGV在培养和原代细胞中有效复制 SIV SGV的感染性和免疫原性 在猕猴模型中。

DESCRIPTION (adapted from applicant's abstract): A successful HIV vaccine must induce a protective HIV-specific CTL response. A live- attenuated HIV vaccine provides a promising strategy to boost the HIV- specific CTL response. Genetically simple derivatives of HIV-l have been proposed as a novel approach to a safe live-attenuated HIV vaccine. The project is based on the hypothesis that infection with HIV structural genes vectors (SGV) provides protective immunity against infection with diverse strains of HIV. The SGV are unique retrovirus vectors that express replication-competent viruses composed of the HIV structural proteins, but lack HIV genes associated with pathogenesis. Because of their unique genetic structure, the SGV are Tat-independent and constitutively replicate HIV gag, pot, env, and a minimal complement of accessory genes. Replication of the SGV provides natural presentation of HIV structural proteins in antigen presenting cells, which assures optimal stimulation of cell-mediated immunity through MHC class I and class II presentation. Limited cycles of replication generate genetic variants important for induction of immunity against diverse strains of HIV, but minimize the chance of a deleterious insertion or recombination event. The HIV SGV are based on prototypic bovine leukemia virus (BLV) SGV that are infectious, immunogenic, and lack pathogenicity in two BLV animal models. The overall goal of this study is to test the hypothesis that SGV are infectious and immunogenic in the surrogate SIV monkey model for AIDS and B-cell Iymphoma. The specific aims are: 1) to define the minimal combination of HIV accessory genes necessary for efficient replication of HIV SGV in cultured and primary cells; 2) to develop similar SIV SGV that replicate efficiently in cultured and primary cells; 3) to evaluate the infectivity and immunogenicity of the SIV SGV in the macaque model.