Molecular mechanisms underlying HIV related intestinal epithelial barrier dysfunction

摘要 本申请中所提出的实验的目标是确定HIV感染如何破坏肠道免疫。 屏障功能现在认识到，微生物易位穿过受损的上皮屏障导致 HIV感染者（PLWH）的循环LPS、持续免疫激活和慢性炎症。 这些HIV相关的影响是神经认知功能过早发育的重要因素。 疾病，心血管疾病，代谢综合征和骨异常，即使在PLWH的最佳 联合抗逆转录病毒治疗（cART）。未经治疗的感染的特征是产生 促炎细胞因子如白细胞介素（IL）-1β、IL-6和肿瘤坏死因子（TNFα）。以下 治疗后，细胞因子水平下降，但慢性炎症仍在继续。预防炎症引起的 合并症需要开发针对潜在病因的更特异性的治疗方法。然而，在这方面， 我们对所涉及的潜在分子途径的理解存在差距。该提案将利用 在艾滋病毒生物学和肠道屏障方面具有专业知识的研究人员之间建立了合作关系， 功能/病理生物学。我们已经生成了强有力的初步数据，为理解 破坏肠上皮屏障功能和HIV感染之间的潜在联系。而整体 HIV感染的慢性炎症表现可能是多因素的，我们令人兴奋的结果支持 固有层HIV-1感染的原代人CD 4 +T淋巴细胞， 与肠上皮细胞相互作用启动导致促炎因子产生增加的过程 细胞因子对上皮内环境稳定产生负面影响，导致肠屏障渗漏。鉴于这些 重要的新见解，要求提供资金，以支持建立一个主要的合作努力， HIV生物学和肠道炎症/屏障破坏领域的研究人员，以确定 原代人肠上皮细胞（IEC）和HIV感染的原代T细胞 协同作用引起肠道病理学。具体来说，我们将确定依赖艾滋病毒的机制， 改变T细胞功能并破坏肠道屏障。此外，我们将确定在IEC中改变的途径， 暴露于HIV感染的T细胞，导致屏障功能障碍。这些研究的结果将 使人们能够更好地了解已知的艾滋病毒相关肠道疾病的潜在机制 艾滋病毒感染者发病率和死亡率的主要来源，并将导致新的 改善艾滋病毒感染者健康的战略。 1

Abstract The goal of proposed experiments in this application is to determine how HIV infection disrupts intestinal barrier function. It is now appreciated that microbial translocation across an impaired epithelial barrier leads to circulating LPS, persistent immune activation and chronic inflammation in people living with HIV (PLWH). These HIV associated effects are important contributors to premature development of neurocognitive disorders, cardiovascular disease, metabolic syndrome and bone abnormalities even in PLWH on optimal combination antiretroviral therapy (cART). Untreated infection is characterized by the production of proinflammatory cytokines such as interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNFα). Following therapy, cytokine levels decline but chronic inflammation continues. Prevention of inflammation-induced comorbidities requires the development of more specific therapeutics targeting the underlying cause. However, a gap exists in our understanding of the underlying molecular pathways involved. This proposal will capitalize on an established collaboration between investigators with expertise in HIV biology and intestinal barrier function/pathobiology. We have generated strong preliminary data that provides a framework for understanding the underlying link between disrupted intestinal epithelial barrier function and HIV infection. While the overall chronic inflammatory manifestations of HIV infection are likely to be multi-factorial, our exciting results support an overarching hypothesis that lamina propria HIV-1 infected primary human CD4+T lymphocytes that closely interact with intestinal epithelial initiate a process leading to enhanced production of pro-inflammatory cytokines that negatively impact epithelial homeostasis resulting in a leaky intestinal barrier. Given these important new insights, funding is requested to support a major collaborative effort between established investigators in the areas of HIV biology and intestinal inflammation/barrier disruption to determine the mechanism(s) through which primary human intestinal epithelial cells (IECs) and HIV-infected primary T cells synergize to cause intestinal pathobiology. Specifically, we will determine the HIV-dependent mechanisms that alter T-cell function and disrupt the intestinal barrier. In addition, we will identify the pathways altered in IECs exposed to HIV infected T-cells that lead to barrier dysfunction. Findings generated from these studies will allow a better understanding of the mechanisms underlying HIV related enteropathy that is known to be a major source of morbidity and mortality in HIV-infected individuals and will lead to development of new strategies to improve the health of HIV infected people. 1