Effect of Helminth Infection on HIV-1 Vaccines

蠕虫感染对 HIV-1 疫苗的影响

• 批准号: 7494355
• 负责人: Donald A Harn
• 金额: $ 40.75万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 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 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7494355
• 关键词: AIDS vaccine development; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Adenovirus Vector; Africa South of the Sahara; Antibodies; Antibody Formation; Automobile Driving; Bacterial Typing; Bacterial Vaccines; Brazil; CD8B1 gene; Calmette-Guerin Bacillus; Cells; China; Clinical Trials; Country; Cytotoxic T-Lymphocytes; DNA Vaccines; Developed Countries; Developing Countries; Development; Disease; Epidemic; Face; Goals; HIV vaccine; HIV-1; HIV-1 vaccine; Helminths; High Prevalence; Human; Immune; Immune response; Immune system; India; Individual; Infection; Joints; Life; Modeling; Mucosal Immunity; Mus; Parasites; Persons; Pharmaceutical Preparations; Play; Population; Populations at Risk; Praziquantel; Prevalence; Public Health; Research Personnel; Role; Route; Schistosoma; Schistosoma mansoni; Schistosoma mansonii infection; Southern Africa; T memory cell; T-Lymphocyte; Testing; Tetanus Toxin; Time; Treatment Protocols; United Nations; Vaccinated; Vaccination; Vaccine Design; Vaccines; Viral; Viral Antigens; Virus; cytotoxic; design; gag Gene Products; immune function; immunoregulation; macrophage; mucosal site; mucosal vaccine; neutralizing antibody; pandemic disease; pathogen; plasmid DNA; programs; research study; response; restoration; success; transmission process; vector vaccine; AIDS vaccine development; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Adenovirus Vector; Africa South of the Sahara; Antibodies; Antibody Formation; Automobile Driving; Bacterial Typing; Bacterial Vaccines; Brazil; CD8B1 gene; Calmette-Guerin Bacillus; Cells; China; Clinical Trials; Country; Cytotoxic T-Lymphocytes; DNA Vaccines; Developed Countries; Developing Countries; Development; Disease; Epidemic; Face; Goals; HIV vaccine; HIV-1; HIV-1 vaccine; Helminths; High Prevalence; Human; Immune; Immune response; Immune system; India; Individual; Infection; Joints; Life; Modeling; Mucosal Immunity; Mus; Parasites; Persons; Pharmaceutical Preparations; Play; Population; Populations at Risk; Praziquantel; Prevalence; Public Health; Research Personnel; Role; Route; Schistosoma; Schistosoma mansoni; Schistosoma mansonii infection; Southern Africa; T memory cell; T-Lymphocyte; Testing; Tetanus Toxin; Time; Treatment Protocols; United Nations; Vaccinated; Vaccination; Vaccine Design; Vaccines; Viral; Viral Antigens; Virus; cytotoxic; design; gag Gene Products; immune function; immunoregulation; macrophage; mucosal site; mucosal vaccine; neutralizing antibody; pandemic disease; pathogen; plasmid DNA; programs; research study; response; restoration; success; transmission process; 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? 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.

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？公共卫生相关性：HIV-1大流行仍然是我们面临的最大的全球疾病威胁之一。大多数受感染的人以及“处于危险”的人群都住在撒哈拉以南非洲和其他发展中国家。已经付出了巨大的努力来为这些人群开发艾滋病毒疫苗，许多人目前正在审判中。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性的蠕虫寄生虫，这些寄生虫已被证明对BCG和TETANUS毒素的疫苗接种产生负面影响。没有人检查过早期蠕虫感染对HIV-1疫苗接种的影响，也没有人检查HIV-1疫苗诱导的免疫反应后发生的情况，并在免疫抑制性这些helminthes中恢复了免疫反应。这项研究旨在回答这两个问题。