Mechanisms of increased susceptibility to TB in HIV-Infected individuals

描述（由申请人提供）：艾滋病毒正在加速结核分枝杆菌（MTB）流行病的急剧增加，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。合并感染可加速两种疾病的自然病程。与大多数其他与艾滋病毒相关的机会性感染不同，结核分枝杆菌感染的风险在感染艾滋病毒后的第一年开始增加。迫切需要更好地了解使艾滋病毒显著增加结核病风险的基本免疫学，以确定发生活动性疾病风险最高的合并感染个体的具体临床和免疫学特征。开发针对艾滋病毒/结核病双重感染者的免疫疗法和治疗性疫苗将大大受益于对结核病和艾滋病毒免疫界面的进一步了解。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，以便最佳地利用治疗资源。结核分枝杆菌的控制是通过细胞介导的免疫，主要涉及CD4+和CD8+ T细胞和抗原呈递细胞（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类型。这为双重感染期间CD4+ T细胞和APC之间的显著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，慢性免疫激活和CD4+ T细胞与APC之间的特异性相互作用导致mtb特异性T细胞频率和功能的丧失，从而增加了重新激活或进行性原发性结核病的风险。我们将以以下目的来检验这一假设：目的1。确定HIV/TB双重感染个体中mtb特异性CD4+和CD8+ T细胞的频率和功能缺陷及其与慢性免疫激活的关系。MTB特异性CD4+和CD8+ T细胞的表型、频率和功能将从一组临床特征良好的乌干达样本中确定，这些样本在MTB反应中产生ifn - γ、IL-2、tnf - α、mip1 - α、CD107a和IL-17的能力。我们可以接触到乌干达的多组受试者进行研究。目标2。利用体外模型确定CD4+细胞、DC细胞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。HIV/TB双重感染对巨噬细胞和DC在免疫突触中将HIV传播到CD4+ T细胞的能力的影响将被确定。目标3。利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失控的特异性细胞相互作用。HIV和MTB的复制将通过使用荧光标记的HIV和MTB活细胞成像显微镜在淋巴组织中进行检查。

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.