Mechanisms of increased susceptibility to TB in HIV-Infected individuals

描述（由申请人提供）：艾滋病毒正在推动M。结核病（MTB）的流行，特别是在撒哈拉以南非洲，其中在一些国家高达70%的结核病（TB）患者合并感染HIV。合并感染可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，M.结核病在感染艾滋病毒后的第一年内开始。 迫切需要更好地了解使艾滋病毒大大增加结核病风险的基本免疫学，以确定最有可能发展为活动性疾病的合并感染个体的特定临床和免疫学特征。针对HIV/TB双重感染个体的免疫疗法和治疗性疫苗的开发将极大地受益于对TB和HIV的免疫界面的更好理解。随着非洲获得艾滋病毒和结核病治疗的机会增加，需要了解这种可能致命的合并感染的免疫学，以便最佳利用治疗资源。 MTB的遏制是通过细胞介导的免疫，主要涉及CD 4+和CD 8 + T细胞和抗原呈递细胞（APC），包括巨噬细胞和树突状细胞（DC）。HIV有效地感染了其中三种细胞类型。这为双重感染期间CD 4 + T细胞和APC之间的显著细胞相互作用提供了背景和机会。我们的总体假设是，在HIV/TB双重感染的情况下，慢性免疫激活和CD 4 + T细胞与APC之间的特异性相互作用导致MTB特异性T细胞的频率和功能丧失，从而增加了再激活或进行性原发性TB的风险。我们将检验这个假设与以下目标：目标1.确定结核分枝杆菌特异性CD 4+和CD 8 + 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CD 4+和CD 8 + T细胞的表型、频率和功能性将从一组充分临床表征的乌干达样品中确定，以确定它们响应于MTB产生IFN-γ、IL-2、TNF-α、MIP 1-α、CD 107 α和IL-17的能力。我们有机会在乌干达进行多组研究。目标二。使用体外模型确定CD 4+细胞、DC和巨噬细胞在双重感染中促进MTB失控的特异性细胞相互作用。将确定HIV/TB双重感染对巨噬细胞和DC将HIV传递给免疫突触中的CD 4 + T细胞的能力的影响。目标3：使用组织外植体模型确定CD 4+细胞、DC和巨噬细胞在双重感染中促进MTB失控的特异性细胞相互作用。我们将使用荧光标记的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。

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.