Macrophage Targeted Therapy for HAD and HIV Disease

描述(由申请人提供)：该计划项目拨款的总体目标是通过研究人类HIV相关痴呆(HAD)模型，确定HIV感染的巨噬细胞在晚期HIV疾病的发病机制中所起的作用，以及长寿的HIV感染巨噬细胞储存库。一类新型药物(多胺生物合成抑制剂，PBI)的体外初步研究表明，选择性地杀伤来自HAD和晚期HIV疾病患者的含有HIV DNA的血液巨噬细胞。在恒河猴免疫缺陷病毒(SIV)脑炎诱导模型上进行的PBI初步研究表明，在体内注射三次药物后，含有SIV的血液和脑组织巨噬细胞选择性地丢失。拟议的研究将由Michael McGrath医学博士协调。在加州大学旧金山分校，他在评估MOS在HIV疾病的发病机制和巨噬细胞靶向药物开发中的作用方面有着悠久的历史。该计划项目将包括体内SIV疾病研究的卓越中心(Ken Williams，哈佛大学)，体内抗HIV和痴呆症药物的临床评估(Valcour，Shikuma，Shiramizu，夏威夷大学)，以及针对HIV DNA储存库和巨噬细胞相关疾病的新诊断和治疗方法的开发(Ken Hadlock，Pathologica LLC，Burlingame CA)。该计划符合RFA-AI-06-009声明的要求，因为它结合了旨在开发新型艾滋病毒疗法的学术和企业研究计划，整合了动物和人类系统的临床前和临床计划。提出了三个项目，每个中心一个，3个核心，用于方案项目赠款。该计划的具体组成部分包括：项目1)PL：肯·哈德洛克，病理有限责任公司。多胺生物合成抑制剂(PBI)杀死/调节HIV感染的巨噬细胞的机制，项目2)PL：Ken Williams，哈佛大学。HAD猴模型中PBI活动的研究，项目3)晚期HIV疾病患者中HIV DNA储存库的临床前和临床研究，HAD)加州大学旧金山分校行政核心A)主任Michael McGrath。该核心负责监督和协调三个项目和另外两个核心中定义的所有研究，分析核心B)董事：Ken Hadlock，病理，有限责任公司。这一核心计划为所有三个项目提供了定量分子分析支持。PBI制药公司核心C)董事：肯·哈德洛克，病理有限责任公司。该核心为所有三个项目提供药物，从项目1和项目3的临床前研究到动物临床研究(项目2)和人类临床研究(项目3)。

DESCRIPTION (provided by applicant): The overall goal of this program project grant is to define the role that HIV infected macrophages play in the pathogenesis of advanced HIV disease, and the long lived HIV infected macrophage reservoir by studying simian models and subsequently humans with HIV associated dementia (HAD). Preliminary studies with a novel class of drugs (polyamine biosynthesis inhibitors, PBI) in vitro showed selective killing of HIV DNA containing blood macrophages from patients with HAD and advanced HIV disease. Initial studies with a PBI in a rhesus monkey simian immunodeficiency virus (SIV) encephalitis induction model showed selective loss of SIV containing blood and brain tissue macrophages in vivo after three injections of drug. The proposed studies will be coordinated by Michael McGrath M.D., PhD. at UCSF who has a long history of evaluating the role of MOs in the pathogenesis of HIV disease and in macrophage targeted drug development. This program project will incorporate centers of excellence for studying SIV disease in vivo (Ken Williams, Harvard), clinical evaluation of anti-HIV and dementia drugs in vivo (Valcour, Shikuma, Shiramizu, U of Hawaii), and the development of novel diagnostic and therapeutic approaches to the HIV DNA reservoir and macrophage associated diseases (Ken Hadlock, Pathologica LLC, Burlingame CA.) This program fulfills requirements of the RFA-AI-06-009 announcement in that it incorporates both academic and corporate research programs aimed at developing novel HIV therapies, integrating both preclinical and clinical programs in animal and human systems. Three projects, one at each center and 3 cores are proposed for the program project grant. Specific components of this program include: Project 1) PL: Ken Hadlock, Pathologica LLC. Mechanism of polyamine biosynthesis inhibitors (PBI) in killing/regulation of HIV infected macrophages, Project 2) PL: Ken Williams, Harvard. Studies of PBI activities in simian models of HAD, Project 3) Preclinical and clinical studies of HIV DNA reservoir in patients with advanced HIV disease and HAD, Administrative Core A) Director Michael McGrath, UCSF. This core provides the oversight and coordination of all of the studies defined in the three projects and two other cores, Assay Core B) Director: Ken Hadlock, Pathologica, LLC. This core program provides quantitative molecular assay support for all three projects. PBI drug manufacture Core C) Director: Ken Hadlock, Pathologica, LLC. This core provides drug for use in all three projects, from the preclinical studies in Projects 1 and 3 to the clinical studies in animals (project 2) and humans (project 3).