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.
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.
