Immune Responses to VSV/HIV/SIV Hybrids in Macaques

6.项目摘要摘要 迫切需要开发一种安全有效的艾滋病毒疫苗。基于疫苗载体的 减毒水泡性口炎病毒(VSV)是细胞和体液的有效诱导物 豁免权。它们可以在SIV-HIV中为恒河猴提供长期的艾滋病保护 混合挑战模型，但不在更严格的SIVmac251挑战模型中。惠氏疫苗 公司将在2008年将基于VSV的减毒HIV疫苗载体转移到临床试验中。虽然VSV 在100多种非人类灵长类动物中，经鼻腔注射的媒介没有显示出致病性， 口服或肌肉注射途径，临床试验的批准一直很慢，因为担心 VSV活载体在人类中的潜在致病性。为了解决这种安全问题，新的高度 基于VSV和混合VSV-Semliki森林病毒(SFV)的减毒或单环载体 繁殖复制子，已经开发出来并在小鼠身上进行了测试，取得了很好的结果。这些向量 也有一个显著的优势，那就是人类对它们没有预先存在的免疫力 人口。这个项目的主要目标是测试这些新矢量在严格的 中和抗体可能发挥保护作用的非人灵长类动物模型 得了艾滋病。在该项目的第一个目标中，基于VSV的单周期启动载体表达 将制备带有和不带有细胞因子GM-CSF的SIVsmE660 Env和Gag蛋白，并 特色化的。已知在启动过程中表达这种细胞因子可以增强记忆T细胞回忆 在小白鼠身上。此外，VSV-SFV杂交复制子颗粒表达相同的Env和 将制备GAG蛋白作为启动子载体。在第二个目标中，将评估这些向量 在恒河猴身上。SIV中和抗体反应和SIV特异性T细胞反应将是 在质数和升压之后进行了详细的评估。接种疫苗的猕猴和对照组将受到挑战 对于致病的SIVsmE660菌株和详细的病毒学和免疫学分析 如果获得保护，则执行以确定保护的相关性。使用SIVsmE660挑战 模型的优点是产生了针对挑战病毒的显著中和抗体 在感染恒河猴期间。如果这些抗体能够在 接种疫苗，有可能推进艾滋病的SIV模型，在该模型中，中和抗体 可能起到有效的作用

6. Project SummaryAbstract There is an urgent need for development of a safe and effective HIV vaccine. Vaccine vectors based on attenuated vesicular stomatitis virus (VSV) are potent inducers of both cellular and humoral immunity. They can provide long-term protection against AIDS in rhesus macaques in an SIV-HIV hybrid challenge model, but not in the more stringent SIVmac251 challenge model. Wyeth Vaccines Inc. is moving attenuated, VSV-based HIV vaccine vectors into clinical trials in 2008. Although VSV vectors have shown no pathogenicity in more than 100 non-human primates when given by nasal, oral, or intramuscular routes, approval for clinical trials has been slow because of concerns about potential pathogenicity of live VSV vectors in humans. To address such safety concerns, new highly attenuated or single-cycle vectors based on VSV and a hybrid VSV-Semliki Forest Virus (SFV) propagating replicon, have been developed and tested in mice with excellent results. These vectors also have the significant advantage that there is no pre-existing immunity to them in the human population. The major goal this project is to test the effectiveness of these new vectors in a stringent non-human primate model in which neutralizing antibody can potentially play a role in protection from AIDS. In the first aim of the project, single-cycle, VSV-based priming vectors expressing SIVsmE660 Env and Gag proteins with and without the cytokine GM-CSF will be prepared and characterized. Expression of this cytokine during priming is known to enhance memory T-cell recall in mice upon boosting. In addition, VSV-SFV hybrid replicon particles expressing the same Env and Gag proteins will be prepared as boosting vectors. In the second aim, these vectors will be evaluated in rhesus macaques. SIV neutralizing antibody responses and SIV-specific T-cell responses will be evaluated in detail following prime and boost. Vaccinated macaques and controls will be challenged with the pathogenic SIVsmE660 strain and detailed virological and immunological analyses will be performed to determine the correlates of protection if it is obtained. Use of the SIVsmE660 challenge model has the advantage that significant neutralizing antibodies to the challenge virus are generated during infection of rhesus macaques. If these antibodies can be generated or primed for during vaccination, there is the potential to advance an SIV model of AIDS in which neutralizing antibody may have an effective role