Role of Myeloid Derived Suppressor Cells in Mycobacterium tuberculosis(Mtb)Reactivation in HIV-Mtb co-infected Individuals

项目摘要 人类免疫缺陷病毒-1（HIV）是结核分枝杆菌（Mtb）的重要危险因素。一 世界上三分之一的人口具有潜伏性结核病感染（LTBI），其中人保持健康。 然而，HIV的存在使LTBI再激活的风险增加了30倍。虽然进行性CD 4 +T 慢性、未经治疗的HIV感染中的细胞耗竭增加了与机会性病原体共感染的风险， 有趣是，HIV感染中的Mtb可以在任何疾病阶段重新激活， 数量很高，病毒复制受到抑制。免疫失调的潜在机制 这增加了艾滋病毒感染者感染结核病和发展活动性结核病的风险， 仍然没有解决。越来越多的证据表明，未经治疗的艾滋病毒感染与艾滋病的传播有关。 CD 11b + CD 33 + CD 14 +HLA DR-/lo髓源性抑制细胞（MDSC）的表达，MDSC是CD 11b + CD 33 + CD 14 +HLA DR-/lo髓源性抑制细胞的介导者。 免疫抑制随着成功的联合抗逆转录病毒治疗（cART），随着CD 4 + T细胞的增加， 当病毒复制被抑制时，MDSC数量下降，但与健康对照相比仍然增加。 我们假设在HIV-Mtb合并感染的个体中，MDSC是免疫缺陷的主要贡献者 分枝杆菌。这一建议的意义在于，我们将利用多方面的方法来研究 HIV-Mtb共感染者MDSC亚群与分枝杆菌相互作用及其比较 分枝杆菌与HLA DRhi亚群的相互作用。我们还提出了控制MDSC的策略 介导的免疫功能障碍。该研究方案结合了Ankita博士的经验和知识 Garg（UCSD，CA，USA）在HIV和Mtb的发病机制和免疫结果中的广泛应用， Luke Hana博士和医生科学家Gopalan Narendran博士在艾滋病毒-结核病合并感染方面的经验 并将提供临床专业知识和标本（均在NIH/NIRT，ICER，Chennai，India）。这将为我们提供 这是一个独特的机会来检验我们的假设，即MDSC对分枝杆菌免疫有害， 是艾滋病毒-结核分枝杆菌合并感染者结核病增加的一个主要因素。通过这次合作 我们还将能够确定是否存在HIV亚型B（美国队列）或亚型C（印度队列） 差异调节MDSC活性和LTBI再活化。提出了两个具体目标：在目标1）中， MDSC中先天效应子功能下调和分枝杆菌负荷增加的机制 从HIV-Mtb共感染个体中分离的病毒将被阐明。目的2）是否存在分枝杆菌特异性T细胞 将研究通过用1，25二羟维生素D3（vit D3）治疗MDSC可以增强的功能。的 拟议研究的长期目标是研究结核病免疫应答的新途径， 艾滋病毒感染的背景。这项研究的成功完成将有助于开发新的诊断方法。 和成本效益的治疗策略，可用于降低艾滋病毒感染者的Mtb风险， 人士

PROJECT SUMMARY Human Immunodeficiency Virus-1 (HIV) is an important risk factor for Mycobacterium tuberculosis (Mtb). One third of the world's population has latent tuberculosis infection (LTBI) where the person remains healthy. However, presence of HIV increases the risk of reactivation of LTBI by 30 fold. Although progressive CD4+T cell depletion in chronic, untreated HIV infection increases the risk of co-infection with opportunistic pathogens, it is intriguing that Mtb in HIV infection can reactivate at any disease stage including times when CD4+ T cell numbers are high and viral replication is suppressed. The underlying mechanism for the dysregulated immunity that increases the risk of acquiring Mtb and developing active tuberculosis (TB) in HIV-infected individuals still remains unresolved. There is increasing evidence that untreated HIV infection is associated with the expansion of CD11b+CD33+CD14+HLA DR-/lo myeloid derived suppressor cells (MDSC) and MDSC are mediators of immune suppression. With successful combined antiretroviral therapy (cART), as CD4+ T cells increase and viral replication is suppressed, MDSC numbers decline but are still increased as compared to healthy controls. We hypothesize that in HIV-Mtb co-infected individuals the MDSC are major contributors of defective immunity to Mycobacterium. The significance of this proposal is that we will utilize a multifaceted approach to study the interaction of Mycobacterium with MDSC subset isolated from HIV-Mtb co-infected individuals and compare it to the interaction of Mycobacterium with HLA DRhi subset. We also propose a strategy to control MDSC mediated immune dysfunction. The research proposal combines the experience and knowledge of Dr. Ankita Garg (UCSD, CA, USA) in the pathogenesis and immunological outcomes of HIV and Mtb with the broad experience of Dr Luke Hana on HIV-Mtb co-infection and Dr Gopalan Narendran who is a physician scientist and will provide clinical expertise and specimens (both at NIH/NIRT, ICER, Chennai, India). This will provide us with a unique opportunity to test our hypothesis that MDSC are detrimental for Mycobacterium immunity and are a major factor for the increase in TB disease in HIV-Mtb co-infected individuals. Through this collaboration we will also be able to identify if presence of HIV subtype B (USA cohorts) or subtype C (Indian cohort) differentially regulates MDSC activity and LTBI reactivation. Two specific aims are proposed: in Aim 1) the mechanisms of downregulated innate effector functions and increased Mycobacterial load in MDSC isolated from HIV-Mtb co-infected individuals will be elucidated. In Aim 2) whether Mycobacterium specific T cell function can be augmented by treating MDSC with 1,25 dihydroxyvitamin D3 (vit D3) will be investigated. The long term goal of the proposed research is to investigate novel pathways in immune response to Mtb in the setting of HIV infection. Successful completion of the study will facilitate the development of novel diagnostic and cost-effective therapeutic strategies that can be adopted to decrease the risk for Mtb in HIV-infected persons.