HIV Vaccines in Th2 Biased Recipients

描述（由申请人提供）：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构建来启动和/或增强th1型细胞毒性CD8+ T细胞，以识别多个HIV-1表位，并诱导中和抗体的正负诱导。由于艾滋病毒/艾滋病的发病率和死亡率最严重的发展中国家人口尤其需要疫苗。驱动艾滋病毒/艾滋病疫苗特异性th1型细胞毒性CD8+ T细胞反应的能力可能受到严重损害，因为发展中国家的大多数个体感染了一种或多种寄生虫，这些寄生虫使免疫系统系统性地倾向于th2型。这项创新建议的重点是分析含有已知小鼠CTL表位的HIV-1候选疫苗在通过感染人类寄生虫血吸虫而产生强烈th2偏向的小鼠中驱动th1型CD8+ T细胞和/或抗体反应的能力。由于正常的免疫偏倚可以通过根除寄生虫恢复，我们打算确定我们的候选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，我们询问在接种候选HIV-1疫苗后在nave小鼠中产生的th1型细胞毒性CD8+ T细胞反应是否可以在面对慢性th2偏向性蠕虫感染时维持。我们假设，长期感染曼氏梭菌的小鼠不会像未感染、接种疫苗的小鼠那样产生期望的th1型、细胞毒性CD8+ T细胞反应。在Aim 1中，我们将确定感染曼氏梭菌的小鼠对候选HIV-1疫苗的反应能力。第二个特异性目标将测试根除蠕虫感染是否恢复疫苗反应性，我们的假设是根除曼氏梭菌感染将使疫苗特异性th1型和细胞毒性CD8+ T细胞对候选HIV-1疫苗产生反应。我们的第三个目标是研究随后的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.