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AIDS-Restrictive Innate Immune Mechanisms

艾滋病限制性先天免疫机制

基本信息

批准号：
8010205
负责人：
WILLIAM H CARR
金额：
$ 12.23万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-12-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8010205
关键词：
AIDS/HIV problem Acquired Immunodeficiency Syndrome Address Adult Affect Africa South of the Sahara African Alleles Area Basic Science Biological Assay Blood specimen Cause of Death Cell Line Cell Surface Proteins Cell Surface Receptors Cells Child Coculture Techniques Collaborations Cross-Sectional Studies Development Development Plans Disease Disease Outcome Disease Progression Drug resistance Educational Curriculum Effectiveness Environment Ethics Ethnic Origin Evaluation General Hospitals Genetic Genetic Variation Goals HIV HIV-1 HLA Antigens HLA-B57 HLA-Bw4 Health Highly Active Antiretroviral Therapy Human Immune Immune Response Genes Immune response Immune system Immunity Immunoglobulins Immunologic Receptors In Vitro Individual Infection Interferons International International Health Problems Isoleucine KIR3DS1 Killer Cells LacZ Genes Ligands Lymphocyte Massachusetts Mediating Medical Research Mentors Molecular Molecular Probes Mothers Mutagenesis Natural Killer Cells Pathogenicity Peptides Play Population Positioning Attribute Pregnancy Prevalence Production RANTES Receptor Gene Reporter Research Research Infrastructure Research Personnel Research Support Role Sampling Screening procedure Site Small Inducible Cytokine A3 South Africa T-Lymphocyte Testing Therapeutic Universities Vertical Disease Transmission Viral Viral Load result Virus Walkers antiretroviral therapy base career career development cell killing drug resistant virus novel peripheral blood pressure receptor research facility response transmission process

项目摘要

DESCRIPTION (provided by applicant): HIV-1 disease is a serious international health problem and a major cause of death in sub-Saharan Africa. Therapeutic and preventative treatments are limited in availability and effectiveness, thus critical evaluations of alternative approaches to control this virus are greatly needed. The overall goal of this project is to elucidate the mechanisms underlying naturally occurring protective immunity to HIV-1 disease in sub- Saharan Africa. The specific aims are (1) to determine the role of NK-cells in decreasing mother to child HIV- 1 transmission and in slowing HIV-1-disease progression to AIDS in adults and (2) to determine the molecular mechanisms of HLA-Bw4 80! mediated protection from HIV transmission and disease progression. In the first aim we will conduct a cross-sectional study by collecting peripheral blood samples from mothers who are HIV-transmitters versus non-transmitters and assessing their NK-cell responses to HIV-infected self and child-derived T cells by the production of anti-viral soluble factors (e.g., interferon-y, MIP-1a & (3, and RANTES) as well as by cell-killing assays. We will also conduct a similar analysis with blood samples from HIV-1-infected adults that are virus controllers compared to virus non-controllers. To address the second aim we will generate reporter cells expressing NFAT-LacZ and the NK cell receptor, KIR3DS1. We will assess HLA-B recognition by KIR3DS1 by in vitro co-culture assays with HIV-1 infected and uninfected target cell lines expressing the putative ligand, HLA-B57. To probe molecular mechanisms of recognition by KIR3DS1 further, HLA mutagenesis or HIV peptide screening will be employed. The research plan is ideal for the career objective of the candidate, William Carr, to become an independent investigator in international health research, specializing in innate viral immunity. The proposed career development plan will consist of closely mentored basic-science research with Drs. Marcus Altfeld and Bruce Walker as mentors in the U.S. and Drs. Hoosen Coovardia and Salim Abdool Karim as a mentors in South Africa, state-of-the-art research facilities at the Doris Duke Research Center in Durban, South Africa, and at the Partners AIDS Research Center at Massachusetts General Hospital in the U.S., and a didactic curriculum on ethics in international research. This plan is well suited for Dr. Carr to establish long-term scientific collaborations in South Africa and to establish himself as an independent investigator in international health research

描述（由申请人提供）：HIV-1 疾病是一个严重的国际健康问题，也是撒哈拉以南非洲地区的一个主要原因。治疗性和预防性治疗的可用性和有效性有限，因此非常需要对控制这种病毒的替代方法进行严格评估。该项目的总体目标是阐明撒哈拉以南非洲地区自然发生的针对 HIV-1 疾病的保护性免疫的机制。具体目标是 (1) 确定 NK 细胞在减少 HIV-1 母婴传播和减缓成人 HIV-1 疾病发展为艾滋病方面的作用，以及 (2) 确定 HLA-Bw4 80! 的分子机制。介导防止艾滋病毒传播和疾病进展的保护。在第一个目标中，我们将进行一项横断面研究，收集 HIV 传播者和非传播者母亲的外周血样本，并通过产生抗病毒可溶性因子（例如干扰素 y、MIP-1a 和（3 和 RANTES）以及细胞杀伤测定来评估她们的 NK 细胞对感染 HIV 的自身和儿童来源的 T 细胞的反应。对病毒控制者和非病毒控制者的 HIV-1 感染成年人的血液样本进行了类似的分析。为了实现第二个目标，我们将生成表达 NFAT-LacZ 和 NK 细胞受体 KIR3DS1 的报告细胞。我们将通过体外共培养测定来评估 KIR3DS1 对 HLA-B 的识别，其中 HIV-1 感染和未感染的靶细胞系表达假定的配体， HLA-B57。为了进一步探究 KIR3DS1 识别的分子机制，将采用 HLA 诱变或 HIV 肽筛选。该研究计划非常适合候选人威廉·卡尔的职业目标，即成为国际健康研究的独立研究者，专门研究先天病毒免疫。拟议的职业发展计划将包括与博士密切指导的基础科学研究。马库斯·阿尔特菲尔德和布鲁斯沃克在美国担任导师，博士。 Hoosen Coovardia 和 Salim Abdool Karim 在南非担任导师，在南非德班的多丽丝杜克研究中心和美国马萨诸塞州总医院的合作伙伴艾滋病研究中心拥有最先进的研究设施，以及国际研究伦理学的教学课程。该计划非常适合卡尔博士在以下领域建立长期科学合作：南非并确立自己作为国际健康研究独立调查员的地位