The impact of TB co-infection on the reservoir of persistent HIV in vivo

结核病合并感染对体内持续性艾滋病毒储存的影响

基本信息

批准号：
9117381
负责人：
PETER W HUNT
金额：
$ 19.68万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9117381
关键词：
Acute Address Aftercare Alveolar Macrophages Anti-Retroviral Agents Antitubercular Agents Blood Cells Bronchoalveolar Lavage Bronchoalveolar Lavage Fluid Cell Lineage Cell Nucleus Cells Clinical Clinical Research DNA DNA Probes Data Detection Disease Enrollment Epidemiology Flow Cytometry Formalin Funding Future Goals Granuloma Granulomatous HIV HIV Infections Health Imagery Immunologist Immunology In Situ Hybridization Individual Lymph Node Tissue Methods Mycobacterium tuberculosis Myelogenous Myeloid Cells Nature Opportunistic Infections Outcome Paraffin Embedding Patients Phagocytosis Phenotype Pneumocystis Pneumocystis carinii Pneumonia Pneumonia Population Prospective Studies RNA RNA Probes Research Research Design Research Personnel Resistance Resolution Role SIV Sampling Shapes Site Source Staining method Stains Structure of parenchyma of lung T-Lymphocyte Technology Time Tissues Trust Tuberculosis United States National Institutes of Health Viral Viral Genome Viral Load result Viral reservoir Virus Replication Visual Whole Blood Work antiretroviral therapy biobank cell type co-infection cohort in vivo lymph nodes macrophage multidisciplinary novel strategies pathogen patient population peripheral blood pulmonary granuloma research study treatment response tuberculosis granuloma tuberculosis treatment

项目摘要

DESCRIPTION (provided by applicant): Recent studies highlight the importance of targeting the persistent HIV reservoir to attain a functional cure. The role of the myeloid cell lineage in maintaining a persistent viral reservoir is poorly understood. Mycobacterium tuberculosis (Mtb) directly infects macrophages, and is associated with increased HIV viral loads and worse clinical outcomes despite treatment for both pathogens. This is unlike other opportunistic infections, such as Pneumocystis Pneumonia (PCP), in which increases in circulating viral loads quickly respond to treatment. Thus, Mtb infection may facilitate the persistence and even expansion of a myeloid reservoir of HIV. Our objective is to describe the myeloid reservoir of HIV in the setting of active tuberculosis (TB) in vivo. To that end, we plan to visually detect HIV DNA and RNA within TB granuloma-associated macrophages and alveolar macrophages, to assess cellular co-localization of DNA or RNA from HIV and Mtb, and to discern whether there is resolution of this putative myeloid reservoir of HIV after treatment for HIV and Mtb. We hypothesize that active or recently active TB will be associated with a sustained reservoir of HIV infection despite treatment for HIV and Mtb; that HIV and Mtb will co-localize within macrophages; and that TB granuloma-associated macrophages will more frequently contain HIV DNA and RNA. Demonstration of a quantifiable Mtb-dependent HIV reservoir within tissue macrophages that persists despite HIV and Mtb treatment will be important for future strategies aimed at HIV eradication, particularly in those many places around the world where TB is rampant. We have assembled a multidisciplinary team of TB researchers and HIV immunologists with expertise in ultra-sensitive methods of HIV detection and clinical study design. Our work leverages existing research cohorts funded by the NIH and the Wellcome Trust, accessing biobanked formalin-fixed paraffin- embedded tissue from HIV-infected subjects with and without active TB, and prospectively collecting bronchoalveolar lavage (BAL) and peripheral blood from subjects with HIV and active TB or HIV and PCP. Samples will be used to: (1) detect and quantify the tissue myeloid reservoir of HIV; (2) assess cellular co- localization o HIV with intracellular Mtb; (3) compare persistence of the alveolar macrophage HIV reservoir in HIV-infected subjects started on ART and recently treated for active TB or acute PCP. Should this exploratory study reveal the existence of an Mtb-specific myeloid reservoir of HIV, we will pursue more comprehensive prospective studies to investigate the mechanisms by which Mtb infection might sustain the persistent HIV reservoir, even in the face of antiretroviral therapy.

描述（由适用提供）：最近的研究突出了针对持续的HIV储藏以获得功能治疗的重要性。髓样细胞谱系在维持持续的病毒储存中的作用知之甚少。结核分枝杆菌（MTB）直接感染了巨噬细胞，并且与两种病原体的HIV病毒载量增加和临床结果较差有关。这与其他机会性感染不同，例如肺炎肺炎肺炎（PCP），其中循环病毒负荷的增加迅速对治疗有反应。这是MTB感染可能有助于促进均为粒细胞的HIV储存剂的持久性甚至扩大。我们的目标是描述体内活性结核病（TB）的HIV的髓样库。为此，我们计划在TB肉芽肿相关的巨噬细胞和肺泡巨噬细胞中视觉检测HIV DNA和RNA，以评估HIV和MTB的DNA或RNA的细胞共定位，并识别该假定的HIV治疗HIV和MTB治疗后，是否可以分辨出这种推定的Myeloid reserevoir of HIV和MTB。我们假设主动或最近活跃的结核病将与HIV和MTB的HIV感染目的地治疗的持续储层有关；艾滋病毒和MTB将在巨噬细胞中共定位； TB肉芽肿相关的巨噬细胞更频繁地含有HIV DNA和RNA。在组织巨噬细胞中可量化的MTB依赖性HIV储量的证明是，持续目的地HIV和MTB治疗对于未来旨在消除HIV的策略至关重要，尤其是在世界各地TB猖ramp的策略中。我们已经组建了一个由结核病研究人员和HIV免疫学家组成的多学科团队，具有在HIV检测和临床研究设计的超敏感方法方面的专业知识。我们的工作利用了由NIH和惠康信托基金会资助的现有研究群体，从具有和没有主动TB的HIV感染受试者的生物链接福尔马林固定的石蜡嵌入式组织，并前瞻性地收集了HIV和活跃的HIV和Active TB或HIV和HIV和PCP的受试者的支气管肺泡灌洗（BAL）和外围血液。样品将用于：（1）检测和量化HIV的组织髓样晶状体；（2）评估细胞内MTB的细胞共定位O HIV；（3）比较肺泡巨噬细胞HIV储存剂在HIV感染受试者中的持久性开始于ART，并最近接受了活跃的TB或急性PCP治疗。如果这项探索性研究揭示了MTB特异性髓样艾滋病毒的存在者的存在，我们将进行更全面的前瞻性研究，以研究MTB感染可能维持持续性HIV储量的机制，即使面对抗逆转录病毒疗法。