Mechanisms of increased susceptibility to TB in HIV-Infected individuals

HIV 感染者对结核病易感性增加的机制

• 批准号: 8435529
• 负责人: DAVID H CANADAY
• 金额: $ 50.48万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8435529
• 关键词: Active Sites; Africa; Africa South of the Sahara; Antigen-Presenting Cells; Antigens; Antitubercular Agents; Asia; CD4 Positive T Lymphocytes; CD8B1 gene; Cell physiology; Cellular Immunity; Cellular biology; Characteristics; Chronic; Clinical; Collaborations; Containment; Country; Data; Defect; Dendritic Cells; Development; Disease; Epidemic; Flow Cytometry; Frequencies; Functional disorder; HIV; HIV Infections; HIV therapy; Health; Health Services Accessibility; Immunologics; Immunology; Immunotherapy; Individual; Infection; Interferon Type II; Interleukin-17; Interleukin-2; Label; Life; Liquid substance; Lung; Lymphoid Tissue; Measures; Microscopy; Modeling; Mycobacterium tuberculosis; Natural History; Opportunistic Infections; Pathogenesis; Patients; Pharmaceutical Preparations; Phenotype; Pleural; Pleural Tuberculosis; Positioning Attribute; Predisposition; Pulmonary Tuberculosis; Regulatory T-Lymphocyte; Research; Research Personnel; Resolution; Resources; Risk; Sampling; Synapses; T-Lymphocyte; Techniques; Tissues; Tuberculosis; Tumor Necrosis Factor-alpha; Uganda; Universities; Vaccines; Viral Tumor Antigens; Work; antiretroviral therapy; cell type; cellular imaging; cohort; combat; human TNF protein; immune activation; improved; in vitro Model; macrophage; pathogen; public health relevance; response; therapeutic vaccine; tool; transmission process; tuberculosis treatment

DESCRIPTION (provided by applicant): HIV is fueling a dramatic increase in the M. tuberculosis (MTB) epidemic particularly in sub-Saharan Africa, where in some countries up to 70% of tuberculosis (TB) patients are co-infected with HIV. Co-infection can accelerate the natural history of both diseases. In contrast to most other opportunistic infections associated with HIV, increased risk with M. tuberculosis begins within the first year after HIV infection. A better understanding of the basic immunology that allows HIV to dramatically increase the risk of TB is urgently needed to identify specific clinical and immunologic characteristics of co-infected individuals at greatest risk for developing active disease. Development of immunotherapy and therapeutic vaccines targeted to HIV/TB dually infected individuals would greatly benefit from an improved understanding of the immunological interface of TB and HIV. As access to treatment for HIV and TB increases in Africa, an understanding of the immunology of this potentially lethal co-infection is needed to allow optimal use of treatment resources. Containment of MTB is through cell-mediated immunity primarily involving CD4+ and CD8+ T cells and antigen presenting cells (APC) including both macrophages and dendritic cells (DC). HIV productively infects three of these cell types. This provides the setting and opportunity for significant cellular interactions between CD4+ T cells and APC during dual infection. Our overall hypothesis is that chronic immune activation and specific interactions between CD4+ T cells and APC in the setting of HIV/TB dual infection results in a loss of frequency and functionality of MTB-specific T cells thereby increasing the risk of reactivation or progressive primary TB. We will examine this hypothesis with the following aims: Aim 1. To determine the frequency and functional defects of MTB-specific CD4+ and CD8+ T cells and their relationship to chronic immune activation in HIV/TB dually infected individuals. The phenotype, frequency, and functionality of MTB-specific CD4+ and CD8+ T cells will be determined from a well clinically characterized set of Ugandan samples in their ability to make IFN-gamma, IL-2, TNF-alpha, MIP1-alpha, CD107a, and IL-17 in response to MTB. We have access to multiple cohorts of subjects in Uganda to study. Aim 2. To determine the specific cellular interactions of CD4+ cells, DC and macrophages that promote loss of control of MTB in dual infection using in vitro models. The effects of HIV/TB dual infection on the ability of macrophages and DC to transmit HIV to CD4+ T cells in the immunologic synapse will be determined. Aim 3. To determine the specific cellular interactions of CD4+ cells, DC and macrophages that promote loss of control of MTB in dual infection using tissue explant models. HIV and MTB replication will we examined in lymphoid tissues by live cell imaging microscopy using fluoro-labeled HIV and MTB.

描述（由申请人提供）：HIV 正在加剧结核分枝杆菌 (MTB) 流行的急剧增加，特别是在撒哈拉以南非洲地区，在一些国家，高达 70% 的结核病 (TB) 患者同时感染 HIV。混合感染可以加速两种疾病的自然病程。与大多数其他与 HIV 相关的机会性感染相比，结核分枝杆菌的风险在感染 HIV 后的第一年内就开始增加。 迫切需要更好地了解艾滋病毒显着增加结核病风险的基本免疫学，以确定最有发展活动性疾病风险的共同感染者的具体临床和免疫学特征。针对艾滋病毒/结核病双重感染者的免疫疗法和治疗性疫苗的开发将极大地受益于对结核病和艾滋病毒免疫学界面的进一步了解。随着非洲艾滋病毒和结核病治疗机会的增加，需要了解这种潜在致命的双重感染的免疫学，以便最佳利用治疗资源。 MTB 的遏制是通过细胞介导的免疫进行的，主要涉及 CD4+ 和 CD8+ T 细胞以及抗原呈递细胞 (APC)，包括巨噬细胞和树突状细胞 (DC)。 HIV有效地感染其中三种细胞类型。这为双重感染期间 CD4+ T 细胞和 APC 之间的显着细胞相互作用提供了环境和机会。我们的总体假设是，在 HIV/TB 双重感染的情况下，慢性免疫激活以及 CD4+ T 细胞和 APC 之间的特异性相互作用会导致 MTB 特异性 T 细胞的频率和功能丧失，从而增加再激活或进行性原发性结核病的风险。我们将通过以下目标检验这一假设： 目标 1. 确定 MTB 特异性 CD4+ 和 CD8+ T 细胞的频率和功能缺陷及其与 HIV/TB 双重感染个体中慢性免疫激活的关系。 MTB 特异性 CD4+ 和 CD8+ T 细胞的表型、频率和功能将根据一组经过充分临床表征的乌干达样本确定其产生 IFN-γ、IL-2、TNF-α、MIP1-α、CD107a 的能力和 IL-17 对 MTB 的反应。我们可以接触到乌干达的多个受试者群体进行研究。目标 2. 使用体外模型确定 CD4+ 细胞、DC 和巨噬细胞在双重感染中促进 MTB 失控的特定细胞相互作用。将确定 HIV/TB 双重感染对巨噬细胞和 DC 将 HIV 传播至免疫突触中 CD4+ T 细胞的能力的影响。目标 3. 使用组织外植体模型确定 CD4+ 细胞、DC 和巨噬细胞在双重感染中促进 MTB 失控的特定细胞相互作用。我们将使用氟标记的 HIV 和 MTB 通过活细胞成像显微镜检查淋巴组织中的 HIV 和 MTB 复制。