Research Article: Progressive Proximal-to-Distal Reduction in Expression of the Tight Junction Complex in Colonic Epithelium of Virally-Suppressed HIV+ Individuals

Date Published: June 26, 2014

Publisher: Public Library of Science

Author(s): Charlotte Y. Chung, Stephanie L. Alden, Nicholas T. Funderburg, Pingfu Fu, Alan D. Levine, Daniel C. Douek.

http://doi.org/10.1371/journal.ppat.1004198

Abstract

Effective antiretroviral therapy (ART) dramatically reduces AIDS-related complications, yet the life expectancy of long-term ART-treated HIV-infected patients remains shortened compared to that of uninfected controls, due to increased risk of non-AIDS related morbidities. Many propose that these complications result from translocated microbial products from the gut that stimulate systemic inflammation – a consequence of increased intestinal paracellular permeability that persists in this population. Concurrent intestinal immunodeficiency and structural barrier deterioration are postulated to drive microbial translocation, and direct evidence of intestinal epithelial breakdown has been reported in untreated pathogenic SIV infection of rhesus macaques. To assess and characterize the extent of epithelial cell damage in virally-suppressed HIV-infected patients, we analyzed intestinal biopsy tissues for changes in the epithelium at the cellular and molecular level. The intestinal epithelium in the HIV gut is grossly intact, exhibiting no decreases in the relative abundance and packing of intestinal epithelial cells. We found no evidence for structural and subcellular localization changes in intestinal epithelial tight junctions (TJ), but observed significant decreases in the colonic, but not terminal ileal, transcript levels of TJ components in the HIV+ cohort. This result is confirmed by a reduction in TJ proteins in the descending colon of HIV+ patients. In the HIV+ cohort, colonic TJ transcript levels progressively decreased along the proximal-to-distal axis. In contrast, expression levels of the same TJ transcripts stayed unchanged, or progressively increased, from the proximal-to-distal gut in the healthy controls. Non-TJ intestinal epithelial cell-specific mRNAs reveal differing patterns of HIV-associated transcriptional alteration, arguing for an overall change in intestinal epithelial transcriptional regulation in the HIV colon. These findings suggest that persistent intestinal epithelial dysregulation involving a reduction in TJ expression is a mechanism driving increases in colonic permeability and microbial translocation in the ART-treated HIV-infected patient, and a possible immunopathogenic factor for non-AIDS related complications.

Partial Text

Chronic systemic inflammation, characterized by increased frequencies of activated B and T cells [1], elevated levels of circulating proinflammatory cytokines and chemokines [2], and more rapid immune cell turnover [3], is a hallmark of HIV/SIV infection and a better predictor of disease progression than plasma viral load [4], [5]. Accumulating evidence suggests that this systemic inflammation plays a role in non-AIDS related comorbidities including cardiovascular diseases [1], [6]–[8], liver diseases [2], [9]–[11], and neurocognitive decline [3], [12], resulting in shortened life expectancy and premature aging in patients treated with long term antiretroviral therapy (ART) [4], [5], [13], [14]. In addition, plasma levels of microbial products, such as lipopolysaccharides (LPS) and bacterial 16s rDNA, are elevated in chronically HIV-infected individuals and associated with markers of immune activation [15]–[17], implicating circulating microbial products, due to microbial translocation, as a major cause of HIV-associated systemic inflammation [18]. An association between circulating microbial products and systemic inflammation has been observed in other disease processes such as inflammatory bowel disease [19], [20] and after laparoscopic surgeries [21], [22]. Moreover, conditioning regimens for stem cell therapy cause gastrointestinal (GI) tract injury that facilitates the translocation of microbial products from the intestinal lumen to systemic circulation, ultimately stimulating the immune system and exacerbating graft-versus-host disease [23], [24]. Klatt et. al. highlight the association between gut epithelial structural damage, local and systemic microbial translocation, and systemic inflammation, in SIV-naïve pigtail macaques [25], suggesting microbial translocation and systemic inflammation as direct consequences of damage to the GI tract in the absence of chronic viral infection.

Microbial translocation from the gut, originating from the enormous quantity of intestinal commensal bacteria, is implicated as a major driver of the chronic systemic inflammation that not only predicts pathogenic HIV disease progression and poor response to ART, but, more importantly, may mediate the immunopathogenesis of non-AIDS morbidities, including cardiovascular, liver, and neurocognitive diseases, that shorten the life expectancy of long-term ART-treated HIV-infected individuals [51], [52]. Elevated microbial translocation is attributed to the simultaneous effects of intestinal mucosal immunodeficiency and disruption to the epithelial barrier, a hypothesis confirmed in pathogenic SIV infection [41]. Structural damage to the intestinal epithelium has been demonstrated in ART-naïve HIV-infected population [53], [54], and we now provide the first direct molecular evidence of gut barrier breakdown in virally-suppressed HIV+ patients, corroborating our clinical data demonstrating persistence of increased intestinal permeability in the ART-treated population [40]. Intestinal epithelial disruption is restricted to the colon and manifests at the molecular level as a down-regulation of the TJ components ZO-1, occludin, claudin-2, and claudin-4, via transcriptional control. The colonic epithelium remains grossly intact, and the packing and relative abundance of epithelial cells are maintained. Moreover, we observed a progressive decline in TJ expression along the proximal-to-distal axis of the HIV+ colon, in contrast to the relatively flat or increasing gradients observed in the healthy intestine. Finally, concurrent alterations in the transcriptional pattern of non-TJ epithelial-specific genes suggest that tight junctional down-regulation in the HIV+ gut occurs as part of an overall intestinal epithelial disruption through modified regulation of transcription.

 

Source:

http://doi.org/10.1371/journal.ppat.1004198

 

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