Microbial Dysbiosis and TLR2 Activation Contribute to Immune Activation, Inflammation and HIV Persistence in the Context of Opioid Abuse Despite ART Therapy

项目摘要 尽管接受了ART治疗，但持续的炎症和免疫激活推动了艾滋病毒疾病的进展。然而， 潜在的机制目前是投机性的，没有清楚地描绘出来。肠道渗漏与微生物 易位是艾滋病毒疾病进展的标志。有趣的是，慢性阿片类药物滥用也很好 被证明会导致肠道渗漏和持续的微生物易位。越来越多的研究 强烈支持这样一个概念，即肠道微生物区系在维持肠道动态平衡和 肠道屏障功能。尽管少数研究已经将HIV感染患者的宿主微生物群与 肠道屏障功能障碍和微生物易位：抗逆转录病毒治疗的后果 治疗(ART)在很大程度上仍未得到探索。目前还没有关于改变的后果的数据 在ART治疗的HIV患者中具有免疫激活和病毒持久性的微生物群 阿片类药物滥用。尽管大多数研究都测量内毒素水平和与革兰氏菌相关的细菌产物- 阴性细菌感染与炎症和艾滋病毒疾病进展有关，最近的研究清楚地表明 HIV感染者体内革兰氏阳性细菌群落的明显丰富和流行 与正常的健康个体相比。我们的初步数据显示， 感染HIV的BLT小鼠中的革兰氏阳性细菌群落，在 阿片类药物治疗。我们的中心假设是革兰氏阳性菌优先扩张的微生物失调 (G+)艾滋病毒感染者和滥用阿片类药物的艾滋病毒感染者的细菌群落 对G+细菌易位，TLR2/TLR4活化，是免疫细胞活化的驱动机制 和持续的炎症导致疾病的进展并阻止恢复正常的健康 在吸食阿片类药物的艾滋病毒感染者中。我们将进一步调查是否使用ART治疗 恢复动态平衡或加剧生物失调。我们将使用NSG-BLT人性化测试我们的假设 在药物滥用和抗逆转录病毒疗法的背景下的艾滋病毒和艾滋病毒的小鼠模型。在具体目标1中，我们将 确定微生物失调、革兰氏阳性细菌群落扩张和肠道渗漏的作用 具有免疫激活和病毒持久性。在特定目标2中，我们将确定TLR-2在 免疫细胞和肠道上皮细胞导致HIV感染后的免疫激活和病毒持续 并在阿片类药物滥用和ART治疗的背景下人源化小鼠。在具体目标3中，我们将确定 益生菌和TLR2拮抗剂的联合治疗将恢复肠道内稳态并减弱 免疫激活，从而在阿片类药物滥用和抗逆转录病毒疗法的背景下延缓艾滋病毒疾病的进展。这个 这些研究的结果将使新的辅助治疗策略的开发成为可能 接受抗逆转录病毒治疗的HIV感染者和HIV感染者的免疫激活和延缓HIV疾病进展 被感染的药物滥用人群。

Project Summary Persistent inflammation and immune activation drive HIV disease progression despite ART therapy. However, the underlying mechanisms are currently speculative and not clearly delineated. Gut leakiness and microbial translocation are hallmarks of HIV disease progression. Interestingly, chronic opioid abuse is also well documented to induce gut leakiness and sustained microbial translocation. Increasing number of studies strongly support the concept that the gut microbiota, play a significant role in maintaining gut homeostasis and gut barrier function. Although a few studies have correlated the host microbiome in HIV infected patients with gut barrier function disruption and microbial translocation, the consequence in the context of antiretroviral treatment (ART) still remains largely unexplored. There is no data on the consequences of an altered microbiome with immune activation and viral persistence in HIV patients on ART therapy in the context of opioid abuse. Although most studies measure endotoxin levels and bacterial products associated with gram- negative bacterial infection with inflammation and HIV disease progression, recent studies clearly show a distinct enrichment and prevalence of gram positive bacterial communities in HIV infected patients when compared to normal healthy individuals. Our preliminary data show significant expansion and translocation of gram positive bacterial communities in HIV infected BLT mice which are further exacerbated in the context of opioid treatment. Our central hypothesis is that microbial dysbiosis with preferential expansion of Gram positive (G+) bacterial communities in HIV infected individuals and HIV infected individuals that are opioid abusers lead to G+ bacterial translocation, TLR2/TLR4 activation and is the driving mechanism for immune cell activation and sustained inflammation contributing to disease progression and preventing the restoration of normal health in HIV-infected individuals that are opioid drug abusers. We will further investigate if treatment with ART restores homeostasis or exacerbates dysbiosis. We will test our hypothesis using NSG-BLT humanized murine model of HIV and HIV in context of substance abuse and ART. In Specific Aim 1 we will determine the role of microbial dysbiosis, expansion of gram-positive bacterial communities and gut leakiness with immune activation and viral persistence. In Specific Aim 2 we will determine that activation of TLR-2 in immune cells and gut epithelial cells results in immune activation and viral persistence following HIV infection and in the context of opioid drug abuse and ART treated humanized mice. In Specific Aim 3 we will determine that combination therapy with Probiotics and TLR2 antagonists will restore gut homeostasis and attenuate immune activation thereby delaying HIV disease progression in the context of opioid abuse and ART. The results from these studies will allow for the development of new adjunct therapeutic strategies to attenuate immune activation and delay HIV disease progression both in HIV infected patients that are on ART and in HIV infected drug abusing population.