Role of the Liver in Microbial Translocation and AIDS Pathogenesis

描述（由申请人提供）：艾滋病患者中微生物易位（MbT）增加的机制在很大程度上尚不清楚。然而，“漏肠综合征”是一个有利的假设，其中管腔细菌和/或其产物破坏上皮细胞的紧密连接，并通过门静脉血和肝脏进入体循环。粘液CD 4 + T细胞，特别是Th 17细胞，在维持肠道上皮屏障的完整性方面起着关键作用，在HIV/SIV感染期间被迅速破坏，并可能有助于MbT。然而，虽然MbT的程度与疾病进展直接相关，但在急性感染期间，当肠道CD 4 T细胞首先耗尽并检测到粘膜损伤时，MbT的程度明显轻微或不存在。因此，HIV/SIV感染引起的CD 4 T细胞急性丢失、粘膜损伤和全身性MbT发作之间存在时间上的脱节。为什么在HIV/SIV感染的急性期肠道上皮屏障可能首先受损时没有观察到全身性MbT？我们推测，在HIV/SIV感染的早期，肝脏，更具体地说，肝脏吞噬细胞，枯否细胞清除微生物产物，阻止大多数微生物产物进入门脉循环进入体循环。我们进一步假设，在致病性HIV/SIV感染的情况下，枯否细胞功能退化，最终导致肝脏清除率降低，使微生物产物进入外周循环，导致慢性免疫激活。为了检验这一假设，我们提出了以下三个具体目标，将利用恒河猴留置门静脉导管：i）未感染，ii）感染致病性SIVmac 239，或iii）感染SIVmac 239的减毒变体（SIVmac 239？戈伊），其不会引起粘膜CD 4 + T细胞的严重持续耗竭。 目的#1：完善非人灵长类动物（NHP）模型，用于：（a）门静脉血的连续采样，（B）肝脏的连续采样，以及（c）确定恒河猴肠道渗透性和微生物产物肝脏清除率的“正常”水平。 目的#2确定急性SIV感染对肠上皮屏障通透性、早期MbT事件、肝功能和肝脏清除“泄漏”管腔微生物产物的能力的影响。 目的#3比较慢性SIV感染与急性SIV感染对肠上皮屏障通透性、早期MbT事件、肝功能、肝脏清除“泄漏”管腔微生物产物的能力的影响，以及这些参数与全身免疫活化标志物的相关性。 公共卫生相关性：由人类免疫缺陷病毒（HIV）引起的获得性免疫缺陷综合症（艾滋病）是一个主要的公共卫生问题。艾滋病发病机制的一个关键特征涉及微生物从肠道易位（MbT）到外周循环，导致慢性免疫激活和艾滋病进展。MbT的发病机制尚未完全了解。该提案将研究肝脏作为控制MbT的“过滤器”的作用。拟议研究的结果可能对我们对艾滋病发病机制的理解产生重大影响，并可能改变治疗个体的方法，以加强肝脏正常“过滤”能力的有效性。

DESCRIPTION (provided by applicant): The mechanism(s) of increased microbial translocation (MbT) in individuals with AIDS is largely unknown. However, the "leaky gut syndrome" is a favored hypothesis, wherein luminal bacteria and/or their products breach the tight junctions of epithelial cells and pass, via the portal blood and liver, into the systemic circulation. Mucosal CD4+ T cells, particularly Th17 cells, that play a critical role in maintaining the integrity of the gut epithelial barrier, are rapidly destroyed during HIV/SIV infection and likely contribute to MbT. However, while the degree of MbT correlates directly with disease progression, it is notably mild or absent during acute infection when gut CD4 T-cells are first depleted and mucosal damage is detected. Therefore, a temporal disconnect exists between the acute loss of CD4 T-cells caused by HIV/SIV infection, mucosal damage and the onset of systemic MbT. Why is systemic MbT not observed in the acute phase of HIV/SIV infection when gut epithelial barriers are likely first damaged? We hypothesize that early in HIV/SIV infection, clearance of microbial products by the liver, and more specifically by hepatic phagocytes, the kupffer cells, prevents most microbial products that enter the portal circulation from accessing the systemic circulation. We further hypothesize that in the setting of pathogenic HIV/SIV infection that kupffer cell function is degraded ultimately resulting in reduced hepatic clearance allowing microbial products to access the peripheral circulation where they lead to chronic immune activation. In order to test this hypothesis we propose the following three specific aims that will utilize indwelling portal vein catheters in rhesus macaques that are: i) uninfected, ii) infected with pathogenic SIVmac239, or iii) infected with an attenuated variant of SIVmac239 (SIVmac239?GY) that does not cause severe sustained depletion of mucosal CD4+ T cells. Aim #1 To refine a nonhuman primate (NHP) model for: (a) serial sampling of portal venous blood, (b) serial sampling of the liver, and (c) determine "normal" levels of gut permeability and liver clearance of microbial products in rhesus macaques. Aim #2 To determine the effect of acute SIV infection on gut epithelial barrier permeability, early MbT events, liver function, and the ability of the liver to clear "leaked" luminal microbial products. Aim #3 To compare the effects of chronic SIV infection to acute SIV infection on gut epithelial barrier permeability, early MbT events, liver function, the ability of the liver to clear "leaked" luminal microbial products, and the association of these parameters with the markers of systemic immune activation. PUBLIC HEALTH RELEVANCE: Acquired Immunodeficiency Syndrome (AIDS) caused by the Human Immunodeficiency Virus (HIV) is a major public health problem. A key feature of the pathogenesis of AIDS involves microbial translocation (MbT) from the intestine to the peripheral circulation causing chronic immune activation and AIDS progression. The pathogenesis of MbT is not well understood. This proposal will examine the role of the liver as a "filter" to control MbT. The results of the proposed studies could have a significant impact on our understanding of AIDS pathogenesis and may change the approach of treating individuals to bolster the effectiveness of the liver's normal "filtering" capacity.