TB-related Immune Reconstitution Syndrome in HIV-1 Infected South Africans

HIV-1 感染南非人中与结核病相关的免疫重建综合征

• 批准号: 7469451
• 负责人: LIVIO AZZONI
• 金额: $ 31.51万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7469451
• 关键词: 5-(6)-carboxyfluorescein diacetate succinimidyl ester; Acquired Immunodeficiency Syndrome; Acute; Address; Africa South of the Sahara; African; Anti-Retroviral Agents; Antigen Presentation; Antigen-Presenting Cells; Binding; Biometry; Blood; CD4 Lymphocyte Count; CD8B1 gene; Caring; Cells; Cellular Immunity; Clinical; Collaborations; Country; Cryptococcus; Cryptosporidium; Dendritic Cells; Diagnosis; Doctor of Philosophy; Frequencies; Future; Graves' Disease; HIV; HIV-1; Health; Hematology; Hospitals; IL3RA gene; ITGAX gene; Immune; Immune response; Individual; Infection; Inflammatory; Institutes; Interferon Type II; Interferons; Laboratories; Ligands; Massachusetts; Measures; Mediating; Memory; Mycobacterium avium; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Myelogenous; Natural Killer Cells; Outcome; Participant; Pathogenesis; Pathology; Patients; Peripheral Blood Mononuclear Cell; Philadelphia; Production; Recovery; Report (document); Research; Sampling; Site; South Africa; Symptoms; Syndrome; Systemic Lupus Erythematosus; T memory cell; T-Lymphocyte; Testing; Time; Toll-Like Receptor 2; Toll-like receptors; Universities; Virus; Week; Whole Blood; antiretroviral therapy; base; clinical Diagnosis; cohort; comparative; cytokine; cytotoxic; early onset; immune function; programs; prospective; reconstitution; response; restoration

DESCRIPTION (provided by applicant): Co-infection with Mycobacterium tuberculosis (MTB) and HIV-1 is a common occurrence in sub-Saharan African Countries. In a significant portion of dual-infected patients initiation of anti-retroviral treatment (ART) results in early onset of clinical and laboratory alterations related to re-acutization of MTB infection, collectively known as Immune Restoration Inflammatory Syndrome (IRIS), the pathogenesis and immune correlates of which are largely unknown at present. We propose to analyze a cohort of HIV-infected individuals developing MTB-related IRIS after ART initiation, by measuring adaptive and innate immune functions. Specifically, we will test the hypotheses that: A- innate immune function, as measured by accessory cell activation (antigen presentation and responsiveness to Toll-like receptors (TLR) 2 7/8 and 9 stimulation) and natural killer cell responses (cytotoxic and cytokine secretion) is directly associated with IRIS and is significantly increased in IRIS patients as compared to non-IRIS HIV-infected controls undergoing ART for comparable periods of time: and B- baseline frequency, activation and function of innate immune effectors may predict a future IRIS outcome in MTB/HIV-1 dual-infected subjects. We will address these hypotheses by comparing the levels of innate and adaptive immune function in whole blood and cryppreserved PBMC from MTB-related IRIS patients and two cohorts of matched non-IRIS, ART-treated controls (asymptomatic or TB co-infected) measuring: A) the frequency of circulating NK subsets, and their IFN-gamma secretion and degranulation responses to interaction with cytokines or target cells. B) the frequency of CD11c myeloid and CD123 plasmacytoid DC, and their cytokine responses to TOLL-like receptor (TLR)-2, 7/8, and 9 binding by specific ligands. C) CD4+ and CD8+ T-cell memory subsets and their proliferative, cytokine and degranulation recall responses to MTB antigens. Completion of this study will provide the first characterization of innate and adaptive correlates to a clinical syndrome that has remained largely unstudied, yet is commonly encountered upon ART initiation in HIV-infected subjects with low CD4 count. Our proposal leverages our unique access to a large cohort (>50 new patients/week) of South African ART-naive patients initiating treatment with CD4 counts under 200 cells/(il, and represents a collaboration between the Wistar Institute (Philadelphia, PA), the "Comprehensive HIV and AIDS Care, Management and Treatment for South Africa" program at the Clinical HIV Research Unit and the Department of Hematology, University of the Witwatersrand (Johannesburg, ZA) and the University of Massachusetts at Amherst.

描述（由申请人提供）：与结核分枝杆菌（MTB）和HIV-1共同感染​​是撒哈拉以南非洲国家的常见情况。在很大一部分受双感染的患者开始抗返回病毒治疗（ART）中，导致与MTB感染的重新效率相关的临床和实验室改变的早期发作（统称为免疫恢复炎症综合征（IRIS）），病原体和免疫相关性目前未知。我们建议通过测量适应性和先天免疫功能来分析在ART启动后开发与MTB相关的IRIS的一组同类。具体而言，我们将测试以下假设：通过辅助细胞激活（抗原呈递和对类似收费的受体的抗原呈递和反应能力）（TLR）2 7/8和9刺激）的假设，自然杀伤细胞反应（TLR）与IRIS相比，与IRIS相比，与IRIS相比，与IRIS相比，自然杀伤细胞反应（细胞毒性和细胞动物分泌）的相关性显着增加，与IRIS相比有了显着控制。时间：和b-基线频率，先天免疫效应子的激活和功能可能预测MTB/HIV-1双感染受试者的未来虹膜结果。我们将通过比较来自MTB相关的IRIS患者的全血和哭泣的PBMC的先天和适应性免疫功能的水平，以及两个匹配的非IRIS，ART治疗的对照组（无症状或TB共同感染）的PBMC，并与他们的IFN nk子集的频率及其相互作用：a）或靶细胞。 b）CD11C髓样和CD123质肽DC的频率，以及它们对Toll样受体（TLR）-2、7/8和9结合的细胞因子反应，特定配体的结合。 c）CD4+和CD8+ T细胞记忆子集及其增殖，细胞因子和脱粒回忆对MTB抗原的反应。这项研究的完成将提供与临床综合征的先天和适应性相关性的首次表征，而临床综合征在很大程度上尚未研究，但通常是在CD4低的HIV感染受试者中遇到的。我们的提议利用了我们独特的南非艺术患者（> 50名新患者/周）的独特获取，该患者对CD4进行治疗，以200个细胞的计数（IL）（IL）进行治疗，并代表了Wistar Institute（Pharadelphia，Pa）（宾夕法尼亚州费城）之间的合作，“全面HIV HIV HIV和AIDS CARE和AID SONDARIGY HAM DOMISTIAL HAM OFINGE SHOLING SORVITIAL HAMING SOMISTIAL HAMING SOMISTIANT和INVING STRICOTION STRICOTINT在IIV的部门和研究部门” （约翰内斯堡，ZA）和阿默斯特的马萨诸塞大学。