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

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.