Effect of Helminth Infection on HIV-1 Vaccines

描述（由申请人提供）：全世界艾滋病流行在发展中国家最为严重，感染人数超过 4000 万人。为南部非洲和其他发展中国家的人口开发 HIV-1 疫苗是当务之急。发展中国家的大多数居民也感染了寄生虫，这些寄生虫会导致 Th2 偏向和免疫抑制。蠕虫感染会抑制对 Th1 型疫苗的免疫反应，以及病毒抗原特异性 CD4 和 CD8 T 细胞反应的扩展。 Th1 型和细胞毒性 CD8 T 细胞反应是大多数正在开发或临床试验中的 HIV-1 候选疫苗的目标。因此，蠕虫感染不仅会影响对候选 HIV-1 疫苗产生强有力的 T 细胞反应，而且会影响这些 T 细胞反应的持久性，这是一个重要的问题。 DNA/腺病毒载体疫苗在驱动全身和/或粘膜疫苗特异性抗体、CD4 和 CD8 T 细胞对 HIV-1 以及其他病原体的反应方面取得了巨大成功。因此，本申请的首要目标是确定 DNA/腺病毒载体 HIV-1 疫苗在消除蠕虫寄生虫后是否会诱导强烈的疫苗特异性 T 细胞反应。为了模仿发展中国家的情况，我们接下来询问这些疫苗特异性 T 细胞反应是否在再次感染蠕虫寄生虫的小鼠中得以维持。在同一方面，我们将确定疫苗接种方案期间的再次感染如何影响疫苗特异性 T 细胞反应的诱导。我们还将确定 F4/80、Gr1 抑制巨噬细胞和/或 CD4、CD25 T 调节细胞是否在抑制蠕虫小鼠中的 HIV-1 疫苗特异性 T 细胞反应中发挥重要作用。最后，由于发展中国家的大多数 HIV-1 传播是通过粘膜部位传播，因此我们想知道蠕虫感染是否对蠕虫感染小鼠的全身性和粘膜 HIV-1 疫苗特异性 T 细胞反应产生不同的影响。该提案的具体目标是： 1) 根除血吸虫感染并恢复正常免疫偏差是否能够在小鼠体内成功接种 HIV-1 候选疫苗？ 2) 针对 HIV-1 疫苗的既定免疫反应会保持持久，还是会因随后的免疫调节性蠕虫感染而改变？ 3) 蠕虫感染对全身性和粘膜性 HIV-1 疫苗特异性 T 细胞反应的影响是否存在差异？

DESCRIPTION (provided by applicant): The worldwide AIDS epidemic is most devastating in developing countries where more than 40 million people are infected. The development of an HIV-1 vaccine for populations in southern Africa and other developing countries is the highest priority. The majority of inhabitants in developing countries are also infected with parasitic helminthes which drive Th2-biasing and immune suppression. Helminth infection suppresses immune responses to Th1-type vaccines, and the expansion of viral antigen specific CD4+ and CD8+ T cell responses. Th1-type and cytotoxic CD8+ T cell responses are the goal of the majority of HIV-1 candidate vaccines in development or in clinical trials. Thus, how helminth infection will impact not only the induction of robust T cell responses to candidate HIV-1 vaccines but also the durability of these T cell responses is an important question. DNA/Adenoviral vector vaccines have shown great success in driving systemic and or mucosal vaccine-specific antibody, CD4+ and CD8+ T cell responses to HIV-1, as well as other pathogens. Thus the first goal of this application is to determine if DNA/Adenoviral vector HIV-1 vaccines will induce strong vaccine specific T cell responses following elimination of helminth parasites. To mimic the scenario in developing countries, we next ask if these vaccine specific T cell responses are maintained in mice that become re-infected with helminth parasites. In this same regard we will determine how re-infection during the vaccination regimen impacts the induction of vaccine specific T cell responses. We will also determine whether F4/80+,Gr1+ suppressor macrophages and/or CD4+,CD25+ T regulatory cells play prominent roles in suppression of HIV-1 vaccine specific T cell responses in helminth mice. Lastly, because the majority of HIV-1 transmission in developing countries is via mucosal sites, we ask if helminth infection differentially impacts systemic vs mucosal HIV-1 vaccine specific T cell responses in helminth infected mice. The specific aims of this proposal are: 1) Will eradication of schistosome infection and restoration of normal immune bias allow for successful vaccination with HIV-1 candidate vaccines in mice? 2) Will established immune responses to HIV-1 vaccines remain durable or be altered by subsequent infection with immunomodulatory helminthes? 3) Does helminth infection differentially impact systemic vs mucosal HIV-1 vaccine specific T cell responses?