Gp120-induced Bob/GPR15 activation: a possible cause of human immunodeficiency virus enteropathy.
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.
Clayton
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Department of Pathology, Salt Lake Veteran's Administration, Salt Lake City, Utah 84148, USA. drfclayton@aol.com
Kotler
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Kuwada
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Morgan
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Stepan
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Kuang
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Le
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Fantini
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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
C103539:GPR15 protein, human; D015699:HIV Envelope Protein gp120; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D012313:RNA; D002118:Calcium