Molecular mechanisms underlying HIV related intestinal epithelial barrier dysfunction

摘要 在这项应用中提出的实验的目标是确定艾滋病毒感染如何扰乱肠道 屏障功能。现在人们认识到，微生物通过受损的上皮屏障易位导致 HIV感染者(PLWH)的循环内毒素、持续免疫激活和慢性炎症。 这些艾滋病毒相关效应是导致神经认知功能过早发育的重要因素。 疾病、心血管疾病、代谢综合征和骨骼异常，即使在PLWH上也是如此 联合抗逆转录病毒疗法(CART)。未经治疗的感染的特点是产生 促炎症细胞因子，如白介素1β、白介素6和肿瘤坏死因子α。跟随 治疗后，细胞因子水平下降，但慢性炎症仍在继续。预防炎症 合并症需要针对根本原因开发更具体的治疗方法。然而， 我们对所涉及的潜在分子途径的理解存在差距。这项提议将使 关于具有艾滋病毒生物学专业知识的研究人员和肠道屏障之间建立的合作 功能/病理生物学。我们已经生成了强大的初步数据，为理解 肠道上皮屏障功能受损与艾滋病毒感染之间的潜在联系。虽然总体上 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 HIV-1固有层感染原代人类CD4T淋巴细胞的重要假说 与肠上皮细胞相互作用启动一个过程，从而增加促炎因子的产生 细胞因子对上皮细胞动态平衡产生负面影响，导致肠道屏障渗漏。考虑到这些 重要的新见解，要求提供资金以支持已建立的 艾滋病毒生物学和肠道炎症/屏障破坏领域的研究人员以确定 原代人肠上皮细胞和HIV感染的原代T细胞的作用机制(S) 协同作用，引起肠道病理生物学。具体地说，我们将确定艾滋病毒依赖的机制 改变T细胞功能，破坏肠道屏障。此外，我们将确定在IECS中改变的路径 暴露在感染艾滋病毒的T细胞中会导致屏障功能障碍。这些研究产生的结果将 让我们更好地了解HIV相关肠病的发病机制 是艾滋病毒感染者发病和死亡的主要来源，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