Role of IL-17 Cytokine Networks in TB Relapse Due to HIV

摘要 结核病（TB）每天夺去4，000人的生命，是由于感染性结核病而导致死亡的主要原因。 疾病然而，在人类免疫缺陷病毒（HIV）感染者中，结核病治疗失败的风险 或治疗后复发率大大增加。结核病复发与药物开发密切相关 艾滋病毒对宿主免疫力的影响知之甚少。了解艾滋病毒因素 因此，推动结核病复发是制定干预措施所需知识的一个重要缺口 支持免疫遏制和补充药物治疗。我们描述了第一个艾滋病毒动物模型- 使用人源化小鼠，在药物治疗后介导的TB复发。我们的初步数据显示， 由于HIV感染导致的IL-17途径活化缺陷是对HIV免疫力丧失的潜在机制。 结核病的病原体，结核分枝杆菌（Mtb）。基于这些发现，我们假设Th 17 T细胞在药物治疗后遏制少杆菌结核病中发挥重要作用， 艾滋病毒感染。我们的合作小组先前进行了HIV+和HIV+中T细胞免疫缺陷的研究。 肯尼亚内罗毕的HIV-人类受试者，他们最近完成了结核病化疗的强化阶段。 我们建议扩大我们的调查，现在证明艾滋病毒状态如何影响Th 17细胞记忆功能 病毒抑制和非抑制人群的结核病化疗后。我们建议进一步利用我们的 HIV介导的TB复发的人源化小鼠模型，以鉴定Th 17细胞和IL-17在 TB遏制，并证明在对Mtb的免疫应答期间Th 17细胞的激活如何促进 病毒在肺中的传播。我们提出以下具体目标：1）目标1，恢复不良或功能障碍， Th 17区室预测HIV受试者化疗后TB复发;和2）Aim 2，HIV 共感染干扰Th 17/IL-17的保护功能，作为结核病药物治疗后驱动Mtb复发的机制 在共感染的人源化小鼠中的治疗。我们希望这些结果能为靶向IL-17细胞因子的研究提供信息。 在制定预防措施方面，鼓励家庭参与，以减少艾滋病毒合并感染导致的结核病复发风险。

Abstract Tuberculosis (TB) claims the lives of 4,000 individuals every day as the leading cause of death due to infectious disease. In those with human immunodeficiency virus (HIV) infection, however, the risk for TB treatment failure or post-therapy relapse is greatly increased. TB relapse is strongly associated with development of drug resistance and occurs through poorly understood effects of HIV on host immunity. Understanding the HIV factors driving TB relapse, then, represents an important gap in knowledge needed for development of interventions that support immune containment and complement drug therapy. We describe the first animal model of HIV- mediated TB relapse following drug treatment, using the humanized mouse. Our preliminary data suggests that defects in activation of IL-17 pathways due to HIV infection are a potential mechanism for loss of immunity to the causative agent of TB, Mycobacterium tuberculosis (Mtb). Based on these findings, we hypothesize that Th17 T cells play an important role in containment of paucibacillary TB following drug therapy that is compromised by HIV infection. Our collaborative group previously conducted investigations of T cell immune defects in HIV+ and HIV- human subjects in Nairobi, Kenya, who had recently completed the intensive phase of TB chemotherapy. We propose to expand our investigations to now demonstrate how HIV status effects Th17 cell memory function following TB chemotherapy in virally suppressed and non-suppressed people. We propose to further use our humanized mouse model of HIV-mediated TB relapse to identify the mechanistic role of Th17 cells and IL-17 in TB containment, and demonstrate how activation of Th17 cells during the immune response to Mtb promotes virus propagation in the lung. We propose the following specific aims: 1) Aim 1, Poor recovery or dysfunction of the Th17 compartment predicts post-chemotherapy TB relapse in human subjects with HIV; and 2) Aim 2, HIV co-infection perturbs protective function of Th17/IL-17 as a mechanism for driving Mtb relapse following TB drug therapy in co-infected humanized mice. We expect these results to inform efforts to target the IL-17 cytokine family in development of preventive measures to reduce TB recurrence in those at risk due to HIV co-infection.