The gastrointestinal manifestations of the acquired immunodeficiency syndrome (AIDS) are of major importance, in view of both frequency and severity of symptoms. In spite of the significance of this clinical problem, investigation of the AIDS enteropathy has been extremely limited. In particular, studies of possible pathogenetic mechanisms have not been performed. The present proposal is aimed at the investigation of the interaction of AIDS causative agent, the human immunodeficiency virus (HIV), with the various cellular components of the gut mucosa and the consequences of such interaction.
The specific aims of this proposal are: (1) to investigate the mechanisms of HIV adherence and penetration in the intestinal mucosa by (a) studying the binding of HIV glycoprotein to intestinal mucus, luminal glycoconjugates, glycoproteins and glycolipids; (b) studying the adherence and penetration of HIV or HIV-derived proteins to organ-cultured intestinal mucosal tissue; and (c) identifying and isolating the microvillous membrane receptor for envelope or other HIV proteins; (2) to investigate the susceptibility of intestinal mucosa to HIV infection by (a) looking for evidence of HIV infection in fresh intestinal tissue of AIDS patients and HIV infected individuals; (b) determining the types of intestinal cells infected in vivo by HIV; and (c) assessing the susceptibility of various intestinal cell types to in vitro infection by HIV; (3) to investigate the effect of HIV on the intestinal immune response by (a) measuring the cytotoxic response of normal intestinal mucosal lymhoid cells against HIV-infected targets; and (b) assessing the phenotypic and functional characteristics of in vivo (patient-derived) and in vitro HIV-infected intestinal mucosal lymphoid cells in regard to cell surface markers, proliferative responses, cytotoxic activity, cytokine and soluble IL2 receptor production and mRNA synthesis. This investigation might uncover basic pathophysiological mechanisms linking specific intestinal mucosal abnormalities to the clinical gastrointestinal manifestations observed in AIDS.
