Gp120-induced Bob/GPR15 activation - A possible cause of human immunodeficiency virus enteropathy

Human immunodeficiency virus (HIV)-infected patients often develop malabsor ption and increased intestinal permeability with diarrhea, called HIV enter opathy, even without enteric opportunistic infections. HIV gp120-induced ca lcium signaling, microtubule loss, and physiological changes resembling HIV enteropathy were previously found in the HT-29 intestinal cell line. How g p120 caused these changes was unclear. We show that the HIV co-receptor Bob /GPR15, unlike CCR5 and CXCR4, Is abundant at the basal surface of small in testinal epithelium. The gp120-induced effects on HT-29 cells were inhibite d by anti Bob neutralizing antibodies, the selective G protein inhibitor pe rtussis toxin, and the phospholipase inhibitor U73122, but not neutralizing antibodies to CXCR4. Gp120 strains that induced signaling in HT-29 cells a lso induced calcium fluxes in Bob-transfected Ghost (3) cells, whereas gp12 0 strains not activating HT-29 cells also did not activate Bob-transfected cells. Bob is the first HIV co-receptor shown to be abundantly expressed on the basolateral surface of intestinal epithelium. Although Bob is an ineff icient infection-inducing co-receptor, it mediates viral strain-specific gp 120-induced calcium signaling at low, physiologically reasonable gp120 conc entrations, up to 10,000-fold lower gp120 concentrations than the principal co-receptors. Gp120-induced Bob activation is a plausible cause of MV ente ropathy.