Effect of Helminth Infection on HIV-1 Vaccines

蠕虫感染对 HIV-1 疫苗的影响

基本信息

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
项目类别：
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

项目摘要

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）：全世界艾滋病流行在发展中国家最为严重，感染人数超过 4000 万人。为南部非洲和其他发展中国家的人口开发 HIV-1 疫苗是当务之急。发展中国家的大多数居民也感染了寄生虫，这些寄生虫会导致 Th2 偏向和免疫抑制。蠕虫感染会抑制对 Th1 型疫苗的免疫反应，以及病毒抗原特异性 CD4+ 和 CD8+ T 细胞反应的扩展。 Th1 型和细胞毒性 CD8+ T 细胞反应是大多数正在开发或临床试验中的 HIV-1 候选疫苗的目标。因此，蠕虫感染不仅会影响对候选 HIV-1 疫苗产生强有力的 T 细胞反应，而且会影响这些 T 细胞反应的持久性，这是一个重要的问题。 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、CD4+ 和 CD8+ T 细胞反应方面取得了巨大成功。因此，本申请的首要目标是确定 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异性 T 细胞反应是否在再次感染蠕虫寄生虫的小鼠中得以维持。在同一方面，我们将确定疫苗接种方案期间的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+ 抑制性巨噬细胞和/或 CD4+、CD25+ T 调节细胞是否在抑制蠕虫小鼠中的 HIV-1 疫苗特异性 T 细胞反应中发挥重要作用。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，因此我们想知道蠕虫感染是否对蠕虫感染小鼠的全身性和粘膜 HIV-1 疫苗特异性 T 细胞反应产生不同的影响。该提案的具体目标是： 1) 根除血吸虫感染并恢复正常免疫偏向是否能够在小鼠体内成功接种 HIV-1 候选疫苗？ 2) 针对 HIV-1 疫苗的既定免疫反应会保持持久，还是会因随后的免疫调节性蠕虫感染而改变？ 3) 蠕虫感染对全身性和粘膜性 HIV-1 疫苗特异性 T 细胞反应的影响是否存在差异？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。人们付出了巨大的努力来为这些人群开发艾滋病毒疫苗，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性蠕虫寄生虫，这些寄生虫已被证明会对卡介苗和破伤风毒素的疫苗接种产生负面影响。没有人研究过早期蠕虫感染对 HIV-1 疫苗接种的影响，也没有研究过再次感染免疫抑制性蠕虫后 HIV-1 疫苗诱导的免疫反应会发生什么情况。本研究旨在回答这两个问题。