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TRANSLATIONAL PHYSIOLOGY

Diarrhea-associated HIV-1 APIs potentiate muscarinic activation of Cl^- secretion by T84 cells via prolongation of cytosolic Ca²⁺ signaling

Paul A. Rufo,^1,5,* Patricia W. Lin,^2,5,* Adriana Andrade,^7, Lianwei Jiang,^3,6,8 Lucia Rameh,⁴ Charles Flexner,⁷ Seth L. Alper,^3,6,8 and Wayne I. Lencer^1,5,8

¹GI Cell Biology, Combined Program in Pediatric Gastroenterology and Nutrition, ²Division of Newborn Medicine, Children's Hospital, ³Molecular and Vascular Medicine and Renal Units and ⁴Division of Signal Transduction, Beth Israel Deaconess Medical Center, and Departments of ⁵Pediatrics and ⁶Medicine, Harvard Medical School, Boston, Massachusetts 02115; ⁷Division of Clinical Pharmacology, Johns Hopkins University, Baltimore, Maryland 21205; and ⁸Harvard Digestive Diseases Center, Boston, Massachusetts 02115

Submitted 22 August 2003 ; accepted in final form 24 December 2003

Aspartyl protease inhibitors (APIs) effectively extend the length and quality of life in human immunodeficiency virus (HIV)-infected patients, but dose-limiting side effects such as lipodystrophy, insulin resistance, and diarrhea have limited their clinical utility. Here, we show that the API nelfinavir induces a secretory form of diarrhea in HIV-infected patients. In vitro studies demonstrate that nelfinavir potentiates muscarinic stimulation of Cl^- secretion by T84 human intestinal cell monolayers through amplification and prolongation of an apical membrane Ca²⁺-dependent Cl^- conductance. This stimulated ion secretion is associated with increased magnitude and duration of muscarinically induced intracellular Ca²⁺ transients via activation of a long-lived, store-operated Ca²⁺ entry pathway. The enhanced intracellular Ca²⁺ signal is associated with uncoupling of the Cl^- conductance from downregulatory intracellular mediators generated normally by muscarinic activation. These data show that APIs modulate Ca²⁺ signaling in secretory epithelial cells and identify a novel target for treatment of clinically important API side effects.

nelfinavir; clotrimazole; barium