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（由申请人提供）：在感染超过4000万人的发展中国家，全球艾滋病流行最具毁灭性。南部非洲和其他发展中国家人口的HIV-1疫苗开发是最高的重中之重。发展中国家的大多数居民还感染了寄生虫，这些寄生虫是驱动Th2偏见和免疫抑制的。蠕虫感染抑制了对Th1型疫苗的免疫反应，并抑制了病毒抗原特异性CD4+和CD8+ T细胞反应的扩展。 Th1型和细胞毒性CD8+ T细胞反应是开发或临床试验中大多数HIV-1候选疫苗的目标。因此，蠕虫感染如何不仅会影响稳健的T细胞对候选HIV-1疫苗的诱导，而且会影响这些T细胞反应的耐用性，这是一个重要问题。 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的反应以及其他病原体方面取得了巨大成功。因此，该应用的第一个目标是确定DNA/腺病毒载体HIV-1疫苗是否会在消除蠕虫寄生虫后诱导强疫苗特异性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定的T细胞反应是否在被蠕虫寄生虫重新感染的小鼠中保持。在同一方面，我们将确定在疫苗接种方案中的重新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HIV-1疫苗特异性T细胞反应中在蠕虫小鼠中起着显着作用。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，因此我们询问蠕虫感染是否会差异地影响全身性与粘膜HIV-1疫苗特异性T细胞反应中的蠕虫感染小鼠。该提案的具体目的是：1）根除血吸虫感染并恢复正常免疫偏见可以使小鼠HIV-1候选疫苗成功疫苗接种？ 2）对HIV-1疫苗的免疫反应是否会保持耐用，或者随后感染免疫调节性蠕虫病？ 3）蠕虫感染是否会差异地影响全身性与粘膜HIV-1疫苗特异性T细胞反应？