Effect of Helminth Infection on HIV-1 Vaccines

描述(申请人提供)：艾滋病在世界范围内的流行在发展中国家是最具破坏性的，那里有4000多万人感染。为南部非洲和其他发展中国家的人口开发艾滋病毒-1疫苗是最优先事项。发展中国家的大多数居民也感染了驱动Th2偏向和免疫抑制的寄生虫。蠕虫感染抑制了对Th1型疫苗的免疫反应，以及病毒抗原特异性CD4和CD8T细胞反应的扩张。Th1型和细胞毒性CD8T细胞反应是大多数HIV-1候选疫苗在开发或临床试验中的目标。因此，蠕虫感染将如何不仅影响对候选HIV-1疫苗的强大T细胞反应的诱导，而且影响这些T细胞反应的持久性是一个重要的问题。DNA/腺病毒载体疫苗在驱动系统和/或粘膜疫苗特异性抗体、HIV-1的CD4和CD8 T细胞反应以及其他病原体方面显示出巨大的成功。因此，这项应用的第一个目标是确定DNA/腺病毒载体HIV-1疫苗在消除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，在再次感染蠕虫寄生虫的小鼠中，这些疫苗特异性T细胞反应是否保持。在这方面，我们将确定疫苗接种期间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、CD25T调节细胞是否在抑制蠕虫小鼠的HIV-1疫苗特异性T细胞反应中发挥显著作用。最后，由于大多数HIV-1在发展中国家的传播是通过粘膜部位，我们询问蠕虫感染是否会对蠕虫感染小鼠的全身和粘膜HIV-1疫苗特异性T细胞反应产生不同的影响。这项建议的具体目的是：1)根除血吸虫感染和恢复正常的免疫偏见是否允许在小鼠中成功接种HIV-1候选疫苗？2)对HIV-1疫苗的已有免疫反应是否持久，或因随后感染免疫调节性蠕虫而改变？3)蠕虫感染是否对全身和粘膜HIV-1疫苗的特异性T细胞反应产生不同的影响？与公共卫生相关：艾滋病毒-1大流行仍然是我们面临的最大全球疾病威胁之一。大多数感染者以及“高危”人群居住在撒哈拉以南非洲和其他发展中国家。为这些人群开发艾滋病毒疫苗做出了巨大努力，许多疫苗目前正在试验中。撒哈拉以南非洲和其他发展中国家的大多数人也感染了免疫抑制蠕虫寄生虫，这些寄生虫已被证明对卡介苗和破伤风毒素疫苗接种产生了负面影响。没有人研究早期蠕虫感染对HIV-1疫苗接种的影响，也没有人研究HIV-1疫苗在再次感染免疫抑制性蠕虫后诱导的免疫反应发生了什么。这项研究旨在回答这两个问题。

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? PUBLIC HEALTH RELEVANCE: The HIV-1 pandemic remains one of the greatest global disease threats we face. The majority of infected individuals as well as the "at-risk" populations reside in sub-saharan Africa and other developing countries. Tremendous effort has been put forth to develop HIV-vaccines for these populations and many are currently in trial. Most of the individuals in sub-saharan Africa and other developing countries are also infected with immune suppressive helminth parasites which have been shown to negatively impact vaccination with BCG and tetanus toxin. No one has examined the impact of earlier helminth infection on HIV-1 vaccination, nor what happens to HIV-1 vaccine induced immune responses following reinfection with immune suppressive helminthes. This study is designed to answer both of these questions.