权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Perturbation of antigen-specific T cell responses in latent TB/SIV co-infection

潜伏 TB/SIV 共感染中抗原特异性 T 细胞反应的扰动

基本信息

批准号：
9198187
负责人：
Deepak Kaushal
金额：
$ 84.38万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
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：
2015-07-01 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9198187
关键词：
Activities of Daily Living Aerosols Antigens Breathing CD4 Lymphocyte Count CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cause of Death Cell Count Cell Degranulation Cell Proliferation Cell physiology Cells Cessation of life Chronic Clinical Cytoplasmic Granules Development Disease Dose Epitopes Equilibrium Experimental Animal Model Frequencies Genetic Transcription Goals Granuloma HIV HIV Infections HIV Seropositivity Homing Human Immune Immune response Immune system Immunity Immunologics Impairment Individual Infection Infection Control Irrigation Lesion Lung MHC Class I Genes Macaca mulatta Maintenance Mediating Memory Modeling Mycobacterium tuberculosis Nature Pathologic Phenotype Population Prevalence Primates Production Regulatory T-Lymphocyte Risk Role SIV Sampling Site Structure of parenchyma of lung T cell response T memory cell T-Lymphocyte Testing Therapeutic Tuberculosis Tuberculosis Vaccines Vaccine Design Viral Load result Whole Blood antiretroviral therapy co-infection cytotoxic experimental study functional disability functional restoration immunopathology in vivo insight killings lifetime risk nonhuman primate peripheral blood preclinical study public health relevance pulmonary granuloma reactivation from latency receptor reconstitution response tool

项目摘要

DESCRIPTION (provided by applicant): Tuberculosis (TB) is the leading cause of death in Human Immunodeficiency Virus (HIV)-infected individuals globally. The majority of HIV-negative individuals infected with Mycobacterium tuberculosis (Mtb) are asymptomatic, and are considered to have latent TB infection (LTBI), providing compelling evidence for host immune control of infection. However, a subset of individuals with LTBI progress to clinically active TB disease when co-infected with HIV. This results from the reactivation of LTBI, potentially due to a loss of control of Mtb within pulmonary granulomatous lesions. Antigen-specific T cells are crucial for controlling Mtb infection in humans and in experimental animal models and lowering of CD4 T cell counts after HIV infection greatly increases the risk of developing TB. However, the mechanisms by which Mtb-specific T cell responses maintain LTBI, confer protective immunity or result in HIV-induced reactivation of LTBI, remain unclear. To develop an effective TB vaccine for populations with high HIV prevalence and to effectively treat Mtb/HIV co- infection, we urgently need to understand how HIV perturbs the latent control of Mtb infection in a chronic state by the primate immune system. We hypothesize that co-infection with HIV depletes and/or impairs in the functional capacities of Mtb-specific CD4 and CD8 T cells to drive reactivation of LTBI and that antiretroviral therapy (ART) only partially restores these functions. We propose to test this hypothesis using mechanistic experiments in the highly human-like nonhuman primate model of inhalation TB. Towards this goal we will i) Define the nature of Mtb-specific CD4 and CD8 T cell responses associated with immune control of Mtb infection in the lungs, BAL and peripheral blood of Indian rhesus macaques with LTBI; ii) Test the hypothesis that co-infection with SIVmac239 progressively impairs Mtb-specific CD4 and CD8 T cell functions, leading to reactivation of LTBI; and iii) Examine the effect of antiretroviral therapy on reconstitution of Mt-specific CD4 and CD8 T cell responses in Mtb/SIV co-infected NHPs.