AIDS-Restrictive Innate Immune Mechanisms

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主要死亡原因。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HIV-1疾病保护性免疫的机制。具体目标是（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AIDS中的作用，以及（2）确定HLA-Bw 4 80！介导的保护免受艾滋病毒传播和疾病进展。在第一个目标中，我们将进行横断面研究，通过收集来自HIV传播者与非传播者的母亲的外周血样品，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）以及细胞杀伤试验。我们还将对来自HIV-1感染成人的血液样本进行类似的分析，这些成人是病毒控制者，而不是病毒非控制者。为了实现第二个目标，我们将产生表达NFAT-LacZ和NK细胞受体KIR 3DS 1的报告细胞。我们将通过与表达推定配体HLA-B57的HIV-1感染和未感染的靶细胞系进行体外共培养测定来评估KIR 3DS 1对HLA-B的识别。为了进一步探索KIR 3DS 1识别的分子机制，将采用HLA诱变或HIV肽筛选。该研究计划是理想的候选人，威廉卡尔的职业目标，成为一个独立的调查员在国际卫生研究，专门研究先天性病毒免疫。拟议的职业发展计划将包括由Marcus Altfeld博士和布鲁斯步行者博士担任美国导师，Hoosen Coovardia博士和Salim Abdool Karim博士担任南非导师，在南非德班的Doris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提供最先进的研究设施，以及关于国际研究中的道德问题的教学课程。这个计划非常适合卡尔博士在南非建立长期的科学合作关系，并使自己成为国际卫生研究的独立调查员

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