Immunity to TB in highly immunosuppressed HIV-infected and uninfected individuals

高度免疫抑制的艾滋病毒感染者和未感染者对结核病的免疫力

• 批准号: 9205082
• 负责人: ANNE GOLDFELD
• 金额: $ 26.97万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-24 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9205082
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Aftercare; Aging; Anti-Retroviral Agents; Antitubercular Agents; Archives; Biological Markers; Blood Cells; CCR6 gene; CD28 gene; CD4 Positive T Lymphocytes; CD8B1 gene; CDKN2A gene; CXCR3 gene; Cambodia; Cambodian; Cause of Death; Cell Count; Cells; Cessation of life; Clinical; DNA Methylation; Data; Differentiation Antigens; Disease; Environment; Epigenetic Process; Exhibits; Frequencies; Future; Growth; HIV; Immune; Immune response; Immune system; Immunity; Immunocompromised Host; Immunophenotyping; Immunosuppression; Individual; Infection; Inflammatory; Intervention; Lead; Life; Lung diseases; Measures; Mediating; Mediator of activation protein; Memory; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Patients; Phenotype; Premature aging syndrome; Proliferating; Pulmonary Tuberculosis; Randomized Clinical Trials; Recruitment Activity; SELL gene; Sampling; Serum; Subgroup; Syndrome; T cell differentiation; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Transcript; Tuberculosis; adaptive immunity; aged; antiretroviral therapy; arm; base; clinical biomarkers; co-infection; cohort; cytokine; design; experience; immunosuppressed; insight; memory CD4 T lymphocyte; methylome; mortality; novel therapeutic intervention; novel therapeutics; patient subsets; peripheral blood; phenotypic biomarker; premature; prophylactic; reconstitution; research study; response; senescence; terminally differentiated effector memory (TEM) T cells; trend; tuberculosis immunity; tuberculosis treatment

Although infection with Mycobacterium tuberculosis (MTb) is the largest cause of pulmonary disease and death in HIV patients globally, little is known about how TB co-infection impacts long-term antiretroviral (ART)- mediated immune reconstitution. The Cambodian Early vs. Late Introduction of Antiretrovirals (CAMELIA) randomized clinical trial showed that early initiation of ART at 2 weeks after TB therapy initiation versus late initiation of ART at 8 weeks in severely immunocompromised TB+/HIV+ patients (median CD4=24/mm3), resulted in a significant (34%) decrease in mortality—a survival benefit that persisted for at least 3 years after the timing intervention. In a scientific sub-study nested within the CAMELIA trial, we have discovered that active TB disease in these highly immunosuppressed TB+/HIV+ patients led to significantly greater pre-ART levels of several pro-inflammatory cytokines and greater pre-ART frequencies of activated CD4+ and CD8+ T cells, and significantly lower pre-ART frequencies of CD28+CD8+ and ICOS+CD4+ T cells, as compared to TB-/HIV+ patients. Moreover, these differences in T cell subset frequencies persisted for at least 8 months after treatment initiation and 2 months after TB cure. Furthermore, we have demonstrated that TB-associated immune reconstitution syndrome (TB-IRIS), which occurred 2.6-fold more frequently in the early CAMELIA treatment arm, results in profound changes in the T cell compartment. For example, TB-IRIS patients exhibited a significant post-ART expansion of (CD62L-CD45RA-) effector memory CD4+T cells and a decrease in (CD62L+CD45RA-) central memory CD4+T cells as compared to non-TB-IRIS patients. We have also found that a Th1-like CD4+ T cell subset that is CXCR3+CCR6+ and thought to mediate a large portion of anti-TB responses was present at significantly elevated frequencies pre-ART in TB-IRIS patients, and the frequency of these cells remained elevated for at least 8 months after treatment onset. Based on our preliminary data, we hypothesize that TB co-infection exacerbates HIV-induced premature aging of the immune system, leading to long-term consequences and poor recall responses. In Aim 1 we will investigate immunosenescent and methylomic signatures in pre-treatment archived samples from TB+/HIV+ CAMELIA and TB-/HIV+ and TB+ /HIV- patients, and in freshly isolated samples from the same patients >5 years after TB treatment and ART initiation. We further hypothesize that within the TB+/HIV+ group the subset of patients who experienced TB- IRIS possessed superior anti-MTb immunity, which was amplified once ART was initiated. In Aim 2 we will compare CXCR3+CCR6+CD4+ T cells in TB-IRIS versus non-TB-IRIS patients to determine their anti-MTb function. Findings from these experiments will provide critical insights into how TB co-infection in HIV+ patients affects phenotypic and epigenetic features of the immune system prior to and following ART-mediated immune reconstitution, and they will elucidate the long-term consequences of TB-IRIS on functional MTb-specific T cell responses that were associated with successful ART-mediated immune reconstitution and TB cure.

虽然感染结核分枝杆菌（MTb）是肺部疾病和死亡的最大原因