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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