AIDS-Restrictive Innate Immune Mechanisms

说明（由申请人提供）：艾滋病毒-1疾病是一个严重的国际卫生问题，也是撒哈拉以南非洲的一个主要死亡原因。治疗性和预防性治疗的可得性和有效性有限，因此非常需要对控制该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自然发生的对HIV-1疾病的保护性免疫的机制。具体目的是：(1)确定nk细胞在减少母婴HIV-1传播和减缓成人HIV-1疾病进展为艾滋病中的作用；(2)确定hla - bw80的分子机制！介导的艾滋病毒传播和疾病进展保护。在第一个目标中，我们将进行一项横断面研究，通过收集hiv传递者与非传递者母亲的外周血样本，通过抗病毒可溶性因子（如干扰素-y、MIP-1a &(3)和RANTES）的产生以及细胞杀伤试验，评估其nk细胞对hiv感染的自身和儿童衍生T细胞的反应。我们还将对hiv -1感染成人的血液样本进行类似的分析，这些成年人是病毒控制者，而非病毒控制者。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。我们将通过与HIV-1感染和未感染的靶细胞系体外共培养试验来评估KIR3DS1对HLA-B的识别，这些靶细胞系表达假定的配体HLA-B57。为了进一步探索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William Carr的职业目标，即成为国际卫生研究领域的独立研究者，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。Marcus Altfeld和Bruce Walker在美国担任导师。Hoosen Coovardia和Salim Abdool Karim作为南非的导师，在南非德班的Doris Duke研究中心和美国马萨诸塞州总医院的Partners艾滋病研究中心提供最先进的研究设施，并在国际研究中开设伦理学教学课程。这项计划非常适合卡尔博士在南非建立长期科学合作，并使他成为国际卫生研究领域的独立研究者

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