HIV This Week

Epple HJ, Schneider T, Troeger H, Kunkel D, Allers K, Moos V, Amasheh M, Loddenkemper C, Fromm M, Zeitz M, Schulzke JD. Impairment of the intestinal barrier is evident in untreated but absent in suppressively treated HIV-infected patients. Gut. 2008 Oct 20. [Epub ahead of print]

Impairment of the gastrointestinal mucosal barrier contributes to progression of HIV infection. Epple and colleagues aimed to investigate the effect of highly active antiretroviral therapy (HAART) on the HIV-induced intestinal barrier defect and to identify underlying mechanisms. 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. Only in untreated but not in treated HIV-infected patients, epithelial resistance was reduced (13(1) versus 23(2)Omegacm2, 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 tumour necrosis factor (TNF)-alpha was increased in untreated but not in treated HIV-infected patients. Incubation with IL-2, IL4, TNF-alpha, and IL-13 reduced the transepithelial resistance of rat jejunal mucosa. 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.

Editors’ note: Chronic immune activation is the main driving force for progressive immune failure in chronic HIV infection. This small study supports the hypothesis that active HIV replication increases inflammatory cytokines in the gut. These impair the epithelial barrier, which then allows gut bacteria and antigens to activate mucosal immunity. Antiretroviral therapy appears to interrupt this self-perpetuating cycle of immune activation and barrier impairment, allowing reconstitution of the gut’s epithelial barrier protective functions.