Effect of Helminth Infection on HIV-1 Vaccines

描述（由申请人提供）：全球艾滋病流行在发展中国家最具破坏性，超过4000万人感染。为南部非洲和其他发展中国家的人口研制艾滋病毒-1疫苗是最高优先事项。发展中国家的大多数居民也感染了寄生蠕虫，这些蠕虫驱动Th 2偏置和免疫抑制。蠕虫感染抑制对Th 1型疫苗的免疫应答，以及病毒抗原特异性CD 4+和CD 8 + T细胞应答的扩增。Th 1型和细胞毒性CD 8 + T细胞应答是大多数HIV-1候选疫苗在开发或临床试验中的目标。因此，蠕虫感染如何不仅影响对候选HIV-1疫苗的稳健T细胞应答的诱导，而且影响这些T细胞应答的持久性是一个重要的问题。DNA/腺病毒载体疫苗在驱动针对HIV-1以及其他病原体的全身和/或粘膜疫苗特异性抗体、CD 4+和CD 8 + T细胞应答方面已经显示出巨大的成功。因此，本申请的第一个目标是确定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细胞应答。为了模拟发展中国家的情况，我们接下来询问这些疫苗特异性T细胞应答是否在再次感染蠕虫寄生虫的小鼠中维持。在这方面，我们将确定疫苗接种方案期间的再感染如何影响疫苗特异性T细胞应答的诱导。我们还将确定F4/80+、Gr 1+抑制性巨噬细胞和/或CD 4+、CD 25 + T调节细胞是否在蠕虫小鼠中抑制HIV-1疫苗特异性T细胞应答中发挥重要作用。最后，因为大多数HIV-1在发展中国家的传播是通过粘膜网站，我们问蠕虫感染是否差异影响系统与粘膜HIV-1疫苗特异性T细胞反应蠕虫感染的小鼠。该提案的具体目标是：1）根除HIV-1感染和恢复正常免疫偏倚是否允许在小鼠中成功接种HIV-1候选疫苗？2)对HIV-1疫苗建立的免疫应答是否会保持持久，或因随后感染免疫调节蠕虫而改变？3)寄生虫感染对系统性与粘膜HIV-1疫苗特异性T细胞应答的影响是否不同？

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?