title: Progressive proximal-to-distal reduction in expression of the tight junction complex in colonic epithelium of virally-suppressed HIV+ individuals.
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.
authors: Departments of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors: Charlotte Y
authors: CY
authors: Chung
authors: Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors: Stephanie L
authors: SL
authors: Alden
authors: The School of Health and Rehabilitation Sciences, Division of Medical Laboratory Science, The Ohio State University College of Medicine, Columbus, Ohio, United States of America.
authors: Nicholas T
authors: NT
authors: Funderburg
authors: Departments of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors: Pingfu
authors: P
authors: Fu
authors: Departments of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America; Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America; Departments of Pathology, Molecular Biology and Microbiology, Pediatrics, and the Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors: Alan D
authors: AD
authors: Levine
mesh_terms: D000046:Academic Medical Centers; D019380:Anti-HIV Agents / Q000009:adverse effects* / Q000627:therapeutic use; D015331:Cohort Studies; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D044682:Colon, Ascending / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000821:virology; D044683:Colon, Descending / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000821:virology; D044684:Colon, Transverse / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000821:virology; D015536:Down-Regulation / Q000187:drug effects*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000821:virology; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008297:Male; D008875:Middle Aged; D009820:Ohio; D009928:Organ Specificity; D010539:Permeability / Q000187:drug effects; D062725:Tight Junction Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000821:virology
chemical_list: D019380:Anti-HIV Agents; D062725:Tight Junction Proteins