HIV-INFECTION OF HUMAN FETAL INTESTINAL EXPLANT CULTURES INDUCES EPITHELIAL-CELL PROLIFERATION

Objective: The concept that HIV infection per se alters small intestin al mucosal structure and function (HIV enteropathy) remains controvers ial and in this study we report in vitro experiments designed to eluci date the matter. Methods: Twenty pairs of human fetal intestinal tissu e explants were maintained in vitro for up to 14 days; one explant of each pair was incubated and infected with HIV, and the other served as a matched uninfected control. At various times after infection, expla nt culture fluid and tissue were removed, p24 concentration was measur ed and tissue formalin fixed. Explant tissue was embedded in paraffin wax and sections stained by an immunoperoxidase method directed agains t proliferating cell nuclear antigen (PCNA). The percentage of prolife rating crypt and villous epithelial cells, stained by PCNA, was calcul ated in paired samples. The difference between the percentage for pair ed samples was designated Delta crypt proliferation (Delta CP) and Del ta villous proliferation (Delta VP), respectively. Epithelial cell pro liferation was deemed to be enhanced if the percentage of PCNA-stained cells was greater in the HIV-infected than in the control tissue. Res ults: Explant culture fluid from tissue exposed to HIV showed a progre ssive rise in p24 antigen (Ag) level, indicating HIV infection of thes e explants. Fifteen pairs of explants showed progressively positive De lta CP with time (P<0.01) indicating crypt hyperplasia and all 20 pair s of explants showed positive Delta VP, indicating hyperplasia of vill ous epithelial cells. Conclusions: This study provides direct evidence that HIV stimulates epithelial cell proliferation in intestinal mucos a. HIV-infected human intestinal explants provide a model of crypt hyp erplastic villous atrophy previously described as HIV enteropathy and detected in clinical biopsy specimens from HIV-infected patients.