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Impairment of the intestinal barrier is evident in untreated but absent in suppressively treated HIV-infected patients
  1. Hans-Joerg Epple (hans-joerg.epple{at}charite.de)
  1. Charite - Universitaetsmedizin Berlin, Campus Benjamin Franklin, Germany
    1. Thomas Schneider (thomas.schneider{at}charite.de)
    1. Charite - Universitaetsmedizin Berlin, Campus Benjamin Franklin, Germany
      1. Hanno Troeger (hanno.troeger{at}charite.de)
      1. Charite - Universitaetsmedizin Berlin, Campus Benjamin Franklin, Germany
        1. Desiree Kunkel (dkunkel{at}pasteur.fr)
        1. Charite - Universitaetsmedizin Berlin, Campus Benjamin Franklin, Germany
          1. Kristina Allers (kristina.allers{at}charite.de)
          1. Charite - Universitaetsmedizin Berlin, Campus Benjamin Franklin, Germany
            1. Verena Moos (verena.moos{at}charite.de)
            1. Charite - Universitaetsmedizin Berlin, Campus Benjamin Franklin, Germany
              1. Maren Amasheh (maren.amasheh{at}charite.de)
              1. Charite - Universitaetsmedizin Berlin, Campus Benjamin Franklin, Germany
                1. Christoph Loddenkemper (christoph.loddenkemper{at}charite.de)
                1. Charite - Universitaetsmedizin Berlin, Campus Benjamin Franklin, Germany
                  1. Michael Fromm (michael.fromm{at}charite.de)
                  1. Charite - Universitaetsmedizin Berlin, Campus Benjamin Franklin, Germany
                    1. Martin Zeitz (martin.zeitz{at}charite.de)
                    1. Charite - Universitaetsmedizin Berlin, Campus Benjamin Franklin, Germany
                      1. Joerg Dieter Schulzke (joerg.schulzke{at}charite.de)
                      1. Charite - Universitaetsmedizin Berlin, Campus Benjamin Franklin, Germany

                        Abstract

                        Objective: Impairment of the gastrointestinal mucosal barrier contributes to progression of HIV infection.

                        Aims: To investigate the effect of highly active antiretroviral therapy (HAART) on the HIV-induced intestinal barrier defect and to identify underlying mechanisms.

                        Methods: Epithelial barrier function was characterized by impedance spectroscopy and 3H-mannitol fluxes in duodenal biopsies from 11 untreated and 8 suppressively treated HIV-infected patients and 9 HIV-seronegative controls. Villus/crypt ratio was determined microscopically. Epithelial apoptoses were analyzed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling and caspase-3 staining. Tight junction protein expression was quantified by densitometric analysis of immunoblots. Mucosal cytokine production was determined by cytometric bead array.

                        Results: Only in untreated but not in treated HIV-infected patients, epithelial resistance was reduced (13(1) versus 23(2)Ωcm2, p<0.01) and mannitol permeability was increased compared to HIV-negative controls (19(3) versus 9(1)nm/s, p<0.05). As structural correlates, epithelial apoptoses and expression of the pore-forming claudin-2 were increased while expression of the sealing claudin-1 was reduced in untreated compared to treated patients and HIV-negative controls. Furthermore, villous atrophy was evident and mucosal production of interleukin (IL)-2, IL-4, and tumor necrosis factor (TNF)-α was increased in untreated but not in treated HIV-infected patients. Incubation with IL-2, IL4, TNF-α and IL-13 reduced the transepithelial resistance of rat jejunal mucosa.

                        Conclusions: Suppressive HAART abrogates HIV-induced intestinal barrier defect and villous atrophy. The HIV-induced barrier defect is due to altered tight junction protein composition and elevated epithelial apoptoses. Mucosal cytokines are mediators of the HIV-induced mucosal barrier defect and villous atrophy.

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