HIV Vaccines in Th2 Biased Recipients

描述(由申请者提供)：HIV-1疫苗正处于临床试验的不同阶段，许多其他疫苗正在开发中。这些疫苗大多利用质粒DNA结构来启动和/或增强，目标是驱动识别多个HIV-1表位的Th1型细胞毒性CD8+T细胞，加上/减去诱导中和抗体。对于艾滋病毒/艾滋病发病率和死亡率最严重的发展中国家人口来说，尤其需要疫苗。驱动HIV/AIDS疫苗特异性Th1型细胞毒性CD8+T细胞反应的能力可能会受到严重损害，因为发展中国家的大多数人感染了一种或多种蠕虫寄生虫，这些寄生虫系统性地使免疫系统偏向Th2型。这项创新建议侧重于分析包含已知的小鼠CTL表位的HIV-1候选疫苗在感染人类寄生虫曼氏血吸虫而产生强烈Th2偏向的小鼠中驱动Th1型CD8+T细胞和/或抗体反应的能力。由于通过根除寄生虫可以恢复正常的免疫偏见，我们建议确定我们的候选HIV-1疫苗是否会在药物治愈的小鼠中驱动Th1型细胞毒性CD8+T细胞反应。最后，我们询问，在以Th2为主的慢性蠕虫感染面前，接种候选HIV-1疫苗后的初生鼠产生的Th1型细胞毒性CD8+T细胞反应是否能够保持。我们假设，慢性感染曼氏葡萄球菌的小鼠不会产生预期的Th1型细胞毒性CD8+T细胞反应，而未感染的接种疫苗的小鼠会出现这种反应。在目标1中，我们将确定感染曼氏葡萄球菌的小鼠对候选HIV-1疫苗的反应能力。第二个具体目标是测试根除蠕虫感染是否恢复了疫苗的反应性，我们的假设是，根除曼氏葡萄球菌感染将使疫苗特异性的Th1型和细胞毒性CD8+T细胞对候选HIV-1疫苗产生反应。我们的第三个目标将检查后续血吸虫感染对已建立的Th1型疫苗反应的影响。

DESCRIPTION (provided by applicant): HIV-1 vaccines are in various phases of clinical trials and numerous others are in the developmental pipeline. Most of these vaccines utilize plasmid DNA constructs to prime and/or boost with the goal of driving Th1-type cytotoxic CD8+ T cells recognizing multiple HIV-1 epitopes, plus/minus induction of neutralizing antibodies. Vaccines are especially needed for developing country populations where morbidity and mortality due to HIV/AIDS is most severe. The ability to drive HIV/AIDS vaccine specific Th1-type cytotoxic CD8+ T cell responses may be severely compromised because the majority of individuals in developing countries are infected with one or more helminth parasites which systemically bias the immune system towards Th2-type. This innovations proposal focuses on analyzing the ability of an HIV-1 candidate vaccine containing a known murine CTL epitope to drive Th1-type CD8+ T cell and/or antibody responses in mice which have been strongly Th2-biased via infection with the human helminth parasite Schistosoma mansoni. Because normal immune bias can be restored by eradication of helminth parasites, we propose to determine if our candidate HIV-1 vaccine will drive Th1-type cytotoxic CD8+ T cell responses in drug-cured mice. Lastly, we ask if Th1-type cytotoxic CD8+ T cell responses generated in nave mice following vaccination with candidate HIV-1 vaccines can be maintained in the face of chronic Th2-biased helminth infection. We hypothesize that mice chronically infected with S. mansoni will not develop the desired Th1-type, cytotoxic CD8+ T cell responses that non-infected, vaccinated mice will. In Aim 1 we will determine the ability of mice infected with S. mansoni to respond to a candidate HIV-1 vaccine. The second Specific Aim will test if eradication of helminth infection restores vaccine responsiveness and our hypothesis is that eradication of S. mansoni infection will enable vaccine-specific Th1-type and cytotoxic CD8+ T cell responses to candidate HIV-1 vaccines. Our third aim will examine the influence of subsequent schistosome infection on an established Th1-type vaccine response.