Role of the Liver in Microbial Translocation and AIDS Pathogenesis

描述（由申请人提供）：艾滋病患者微生物易位（MbT）增加的机制在很大程度上是未知的。然而，“漏肠综合征”是一个受欢迎的假说，其中肠道细菌和/或它们的产物破坏上皮细胞的紧密连接，并通过门静脉血液和肝脏进入体循环。粘膜CD4+ T细胞，特别是Th17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感染期间迅速被破坏，并可能导致MbT。然而，尽管MbT的程度与疾病进展直接相关，但在急性感染期间，当肠道CD4 t细胞首次耗尽并检测到粘膜损伤时，MbT明显轻微或不存在。因此，在HIV/SIV感染引起的CD4 t细胞急性损失、粘膜损伤和全身性MbT发病之间存在时间脱节。为什么在肠道上皮屏障可能首先受损的HIV/SIV感染急性期未观察到全身性MbT ？我们假设在HIV/SIV感染的早期，肝脏清除微生物产物，更具体地说是肝脏吞噬细胞（kupffer细胞），阻止大多数进入门静脉循环的微生物产物进入体循环。我们进一步假设，在致病性HIV/SIV感染的情况下，库普弗细胞功能退化最终导致肝脏清除减少，从而使微生物产物进入外周循环，从而导致慢性免疫激活。为了验证这一假设，我们提出了以下三个具体目标，将在恒河猴中使用留置门静脉导管：i)未感染，ii)感染致病性SIVmac239，或iii)感染SIVmac239的减毒变体(SIVmac239？GY)不会引起黏膜CD4+ T细胞严重的持续耗竭。

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.