title: Gp120-induced Bob/GPR15 activation: a possible cause of human immunodeficiency virus enteropathy.
abstract: Human immunodeficiency virus (HIV)-infected patients often develop malabsorption and increased intestinal permeability with diarrhea, called HIV enteropathy, even without enteric opportunistic infections. HIV gp120-induced calcium signaling, microtubule loss, and physiological changes resembling HIV enteropathy were previously found in the HT-29 intestinal cell line. How gp120 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 intestinal epithelium. The gp120-induced effects on HT-29 cells were inhibited by anti-Bob neutralizing antibodies, the selective G protein inhibitor pertussis toxin, and the phospholipase inhibitor U73122, but not neutralizing antibodies to CXCR4. Gp120 strains that induced signaling in HT-29 cells also induced calcium fluxes in Bob-transfected Ghost (3) cells, whereas gp120 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 inefficient infection-inducing co-receptor, it mediates viral strain-specific gp120-induced calcium signaling at low, physiologically reasonable gp120 concentrations, up to 10,000-fold lower gp120 concentrations than the principal co-receptors. Gp120-induced Bob activation is a plausible cause of HIV enteropathy.
authors.affiliation: Department of Pathology, Salt Lake Veteran's Administration, Salt Lake City, Utah 84148, USA. drfclayton@aol.com
authors.forename: F
authors.initials: F
authors.lastname: Clayton
authors.forename: D P
authors.initials: DP
authors.lastname: Kotler
authors.forename: S K
authors.initials: SK
authors.lastname: Kuwada
authors.forename: T
authors.initials: T
authors.lastname: Morgan
authors.forename: C
authors.initials: C
authors.lastname: Stepan
authors.forename: J
authors.initials: J
authors.lastname: Kuang
authors.forename: J
authors.initials: J
authors.lastname: Le
authors.forename: J
authors.initials: J
authors.lastname: Fantini
mesh_terms: D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology* / Q000502:physiology; D015658:HIV Infections / Q000150:complications; D006801:Humans; D007158:Immunologic Techniques; D017403:In Situ Hybridization; D007410:Intestinal Diseases / Q000821:virology*; D007422:Intestines / Q000187:drug effects / Q000473:pathology; D008870:Microtubules / Q000187:drug effects / Q000473:pathology; D012313:RNA / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide / Q000502:physiology*; D013194:Staining and Labeling; D014407:Tumor Cells, Cultured
chemical_list: C103539:GPR15 protein, human; D015699:HIV Envelope Protein gp120; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D012313:RNA; D002118:Calcium