Direct effect of type 1 human immunodeficiency virus (HIV-I) on intestinal epithelial cell differentiation: Relationship to HIV-I enteropathy

Human immunodeficiency Virus (HIV)-infected patients display severe impairments of gastrointestinal functions, including diarrhea and malabsorption, even in the absence of opportunistic infections. Since HIV-I proteins and nucleic acids have been detected in several cell types of the intestinal mucosa, it has been postulated that HIV-I itself could alter enterocytic functions. In the present study, we analyzed the effect of HIV-I on the differentiation process of the epithelia[ intestinal cell clone HT-29-D4, which mimics the maturation of enterocytes along the crypt-villus axis of the small intestine. We found that HIV-1 infection impairs cellular differentiation (i) by affecting the barrier function of the epithelium, as evidenced by a decrease in the transepithelial electrical resistance, and (ii) by inhibiting the activity of one major glucose absorption function, i.e., sodium/glucose cotransport At the morphological level, HIV-I infection of HT-29-D4 cells was associated with the formation of lumina, which are representative of a defect in cellular organization. These morphofunctional perturbations induced by HIV-1 could be mimicked by nocodazole, a microtubule-disrupting agent Correspondingly, HIV-1 exposure of HT-29-D4 cells evoked a massive disruption of microtubules, as revealed by alpha-tubulin indirect immunofluorescence staining. A similar effect was observed after incubation of the cells with either recombinant gp120 or a monoclonal antibody against galactosylceramide (GalCer), the intestinal receptor for HIV-1 gp120, suggesting that the effect of HIV-1 was mediated by the binding of gp120 to GalCer. Based on these data, we propose that HIV-I may selectively alter enterocytic functions through a direct effect on the intracellular architecture of the cells. in contrast with previous theories for HIV-I enteropathy, our data support the concept that HIV-I may perturb intestinal functions without necessarily infecting intestinal epithelial cells. (C) 1997 Academic Press.