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(American Journal of Pathology. 2001;159:1933-1939.)
© 2001 American Society for Investigative Pathology

Regular Articles

Gp120-Induced Bob/GPR15 Activation

A Possible Cause of Human Immunodeficiency Virus Enteropathy

Frederic Clayton^*, Donald P. Kotler, Scott K. Kuwada^¶, Terry Morgan, Caleb Stepan^*, Jinqiu Kuang^¶, James Le^* and Jacques Fantini^||

From the Departments of Pathology^*
and Medicine,
, Salt Lake Veteran’s Administration, Salt Lake City, Utah; the Departments of Pathology
and Medicine,^¶
University of Utah School of Medicine, Salt Lake City, Utah; the Division of Gastroenterology,
St. Luke’s/Roosevelt Hospital and Columbia University, New York, New York; and the Faculté des Sciences St-Jérôme,^||
Institut Mediterranéen de Recherche en Nutrition, Marseilles, France

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.

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