Effect of Helminth Infection on HIV-1 Vaccines

蠕虫感染对 HIV-1 疫苗的影响

• 批准号: 8013546
• 负责人: Donald A Harn
• 金额: $ 36.39万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-15 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8013546
• 关键词: Acquired Immunodeficiency Syndrome; Adenovirus Vector; Antibodies; Automobile Driving; CD8B1 gene; Clinical Trials; DNA; Developing Countries; Development; Epidemic; Goals; HIV-1; Helminths; IL2RA gene; Immune; Immune response; Immunosuppression; Infection; Mus; Names; Parasites; Play; Population; Principal Investigator; Regimen; Regulatory T-Lymphocyte; Research; Role; Schistosoma; Southern Africa; T cell response; Vaccination; Vaccines; Viral Antigens; cytotoxic; macrophage; mucosal site; mucosal vaccine; pathogen; programs; restoration; success; transmission process; vaccine candidate; vector vaccine

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?

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CD8+T细胞反应的扩大。Th1型和细胞毒性CD8+T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、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+、CD25+T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？