Mechanisms of increased susceptibility to TB in HIV-Infected individuals

描述(申请人提供)：艾滋病毒正在加剧结核分枝杆菌(MTB)疫情的急剧增加，特别是在撒哈拉以南非洲，在一些国家，高达70%的结核病(TB)患者合并感染艾滋病毒。混合感染会加速这两种疾病的自然病程。与大多数其他与艾滋病毒有关的机会性感染不同，结核分枝杆菌感染的风险增加在艾滋病毒感染后的第一年内就开始增加。迫切需要更好地了解使艾滋病毒大幅增加结核病风险的基本免疫学，以确定最有可能罹患活动性疾病的合并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更好地了解结核病和艾滋病毒的免疫学接口。随着非洲艾滋病毒和结核病治疗机会的增加，需要了解这种潜在的致命混合感染的免疫学，以便能够最佳地利用治疗资源。对结核分枝杆菌的控制主要是通过细胞免疫，主要涉及CD4+和CD8+T细胞和抗原提呈细胞(APC)，包括巨噬细胞和树突状细胞(DC)。艾滋病毒可以有效地感染其中三种细胞。这为双重感染期间CD4+T细胞和APC之间显著的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双重感染的背景下，CD4+T细胞和APC之间的慢性免疫激活和特异性相互作用导致MTB特异性T细胞的频率和功能丧失，从而增加再次激活或进行性原发结核病的风险。我们将通过以下目的验证这一假说：目的1.确定结核分枝杆菌特异性CD4+和CD8+T细胞在HIV/TB双重感染者中的频率和功能缺陷及其与慢性免疫激活的关系。MTB特异性的CD4+和CD8+T细胞的表型、频率和功能将从一组具有良好临床特征的乌干达样本中确定，这些样本能够产生针对MTB的干扰素-γ、IL-2、肿瘤坏死因子-α、MIP1-α、CD107a和IL-17。我们可以接触到乌干达的多个学科群进行研究。目的2.利用体外实验模型，确定在双重感染中，促进结核分枝杆菌失控的CD4+细胞、DC和巨噬细胞之间的特异性细胞相互作用。HIV/TB双重感染对巨噬细胞和DC将HIV传递给免疫突触中的CD4+T细胞的能力的影响将被确定。目的3.利用组织块模型，确定在双重感染中促进结核分枝杆菌失控的CD4+细胞、DC和巨噬细胞之间的特异性细胞相互作用。我们将使用氟标记的HIV和MTB通过活细胞成像显微镜在淋巴组织中检测HIV和MTB的复制。 公共卫生相关性：该项目将帮助理解感染艾滋病毒如何显著增加患结核病(TB)的风险。结核病和艾滋病毒双重感染是一个非常严重的健康问题，特别是在非洲和亚洲。这项工作可能有助于开发更好的疫苗和药物来对抗这种联合感染。

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. PUBLIC HEALTH RELEVANCE: This project will help understand how becoming HIV infected dramatically increases the risk of developing tuberculosis (TB) disease. Dual infection with TB and HIV is a very significant health problem particularly in Africa and Asia. This work could aid in the development of better vaccines and drugs to combat this co-infection.