Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 159, Issue 5, Pages 1933-1939Publisher
AMER SOC INVESTIGATIVE PATHOLOGY, INC
DOI: 10.1016/S0002-9440(10)63040-4
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- NIAID NIH HHS [AI211414] Funding Source: Medline
- NIDDK NIH HHS [K08-DK-02531] Funding Source: Medline
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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 MV enteropathy.
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