The impact of the HIV reservoir on pulmonary myeloid cells: virology, phenotype, and function

项目摘要/摘要 这是一份K01奖的申请书，授予医学博士约书亚·巴斯克斯博士， 加州大学实验医学和肺与危重病医学部 旧金山，他正在确立自己作为艾滋病毒免疫学临床医生和科学家的地位。他的目标是应用他的 肺医学背景来自一项研究肺源性疾病基础机制的临床联谊会 艾滋病治疗中的炎症和免疫功能障碍。这一奖项将为他提供支持， 完成以下目标：(1)确定艾滋病毒的肺部宿主的特征和(2)确定 负责巡逻肺泡的肺泡巨噬细胞持续存在表型和功能缺陷- 毛细血管屏障，尽管进行了抗逆转录病毒治疗，特别是在那些CD4+T细胞最低点较低的患者。要实现 在这些目标中，他将有四位共同导师，他们各自具有独特的优势和既定的记录 富有成效的科学调查和对研究人员的指导。他的主要导师是彼得·亨特博士， 加州大学旧金山分校扎克伯格综合医院实验医学部临时主任， 和国际公认的艾滋病毒翻译免疫学专家，特别是机制和 在治疗艾滋病毒期间慢性炎症的后果。瓦斯克斯博士还将与合作导师一起工作 约瑟夫(迈克)麦库恩博士，一位杰出的免疫学家，进行了许多关于艾滋病毒的开创性研究 发病机制；克利福德·洛厄尔博士，实验室医学主席，公认的细胞内专家 调节先天免疫系统炎症的信号通路；以及劳伦斯·黄博士 国际公认的艾滋病毒肺部并发症专家。他还积极参与了 将继续在以下领域提供重点支持的合作者：艾滋病毒组织储存库评估 聚合酶链式反应(Steven Yukl博士)、艾滋病毒相关组织病理学(Zoltan Laszik博士)、肺泡巨噬细胞免疫学 (Mehrda Arjomandi博士)，生物统计学(Peter Bacchetti博士)，肺部免疫学(Prescott Woodruff博士)， 以及质量细胞术和高维计算分析(马修·斯皮策博士)。作为这件事的一部分 获奖后，他将继续接受翻译研究、免疫学方法和生物信息学方面的额外培训。 利用对独特患者样本的获取，他将应用现有的和新的免疫学技术来 确定在HIV疾病的背景下肺泡巨噬细胞程序是如何改变的。这些研究的结果 研究应该广泛适用于我们对其他常见疾病的组织免疫学的理解 并有助于指导以髓系细胞为靶点的免疫调节疗法的发展。最终， 这里概述的培训和研究计划将支持他从基础免疫学家和 将临床肺/重症监护专家转变为具备以下技能的转化型研究人员 独立的职业生涯，专注于阐明髓系细胞生物学的基本原理，并为 传染病疗法和疫苗的发展。

PROJECT SUMMARY/ABSTRACT This is an application for a K01 award for Dr. Joshua Vásquez, MD, Assistant Professor in the Division of Experimental Medicine and the Division Pulmonary and Critical Care Medicine at the University of California at San Francisco who is establishing himself as a clinician-scientist in HIV immunology. His goal is to apply his pulmonary medicine background from a clinical fellowship to study the mechanisms that underlie pulmonary inflammation and immune dysfunction in treated HIV disease. This award will provide him with the support to accomplish the following goals: (1) to characterize the pulmonary reservoir of HIV and (2) to determine whether phenotypic and functional defects persist in alveolar macrophages responsible for patrolling the alveolar- capillary barrier, despite antiretroviral therapy, particularly among those with low CD4+ T cell nadirs. To achieve these goals, he will have four co-mentors who each have unique strengths and established track records of productive scientific investigation and mentorship of research fellows. His primary mentor is Dr. Peter Hunt, the interim chief of the Division of Experimental Medicine at UCSF/Zuckerberg San Francisco General Hospital, and an internationally-recognized expert in HIV translational immunology, specifically the mechanisms and consequences of chronic inflammation during treated HIV disease. Dr. Vasquez will also work with co-mentors Dr. Joseph (Mike) McCune, a preeminent immunologist who has conducted many seminal studies in HIV pathogenesis; Dr. Clifford Lowell, Chair of Laboratory Medicine and a recognized expert on intracellular signaling pathways regulating inflammation in the innate immune system; and Dr. Laurence Huang, an internationally-recognized expert in the pulmonary complications of HIV disease. He has also engaged active collaborators who will continue to provide focused support in the areas of: HIV tissue reservoir assessment by PCR (Dr. Steven Yukl), HIV-associated tissue pathology (Dr. Zoltan Laszik), alveolar macrophage immunology (Dr. Mehrdad Arjomandi), biostatistics (Dr. Peter Bacchetti), pulmonary immunology (Dr. Prescott Woodruff), as well as mass cytometry and high dimensional computational analysis (Dr. Matthew Spitzer). As a part of this award, he will pursue additional training in translational research, immunology methods, and bioinformatics. Leveraging access to unique patient samples, he will apply existing and novel immunologic techniques to determine how alveolar macrophage programs are altered in the setting of HIV disease. The results of these studies should be widely applicable to our understanding of the tissue immunology of other common diseases and be useful to guide the development of immunomodulatory therapies targeted at myeloid cells. Ultimately, the training and research plans outlined here will support his transition from being a basic immunologist and clinical pulmonary/critical care specialist to being a translational researcher equipped with the skills to pursue an independent career focused on elucidating the fundamental principles of myeloid cell biology and informing the development of therapeutics and vaccines for infectious diseases.