HIV envelope gp120 activates human arterial smooth muscle cells

doi:10.1073/pnas.181328798

HIV envelope gp120 activates human arterial smooth muscle cells

^*Zena and Michael A. Wiener Cardiovascular Institute and Departments of ^‡Medicine, ^**Microbiology, and ^‡‡Physiology and Biophysics, Division of Infectious Diseases, Mount Sinai School of Medicine, New York, NY 10029; ^§DuPont Pharmaceuticals, Experimental Station, Wilmington, DE 19803; and Departments of ^¶Pathology and ^‖Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461

Communicated by Peter Palese, Mount Sinai School of Medicine, New York, NY (received for review February 13, 2001)

Abstract

There have been increasing reports of acute coronary thrombotic events in patients with HIV. Although these clinical events have been attributed primarily to dyslipidemia associated with protease inhibitor therapy, autopsy studies in children with HIV suggest the presence of an underlying arteriopathy. This study demonstrates that the HIV envelope protein, gp120, activates human arterial smooth muscle cells to express tissue factor, the initiator of the coagulation cascade. The induction of tissue factor by gp120 is mediated by two biologically relevant coreceptors for HIV infection, CXCR4 and CCR5, and is also dependent on the presence of functional CD4. Induction of tissue factor by gp120 requires activation of mitogen-activating protein kinases, activation of protein kinase C, and generation of reactive oxygen species, signaling pathways that have protean effects on smooth muscle cell physiology. The activation of smooth muscle cells by gp120 may play an important role in the vascular, thrombotic, and inflammatory responses to HIV infection.

Footnotes

↵ † To whom reprint requests should be addressed. E-mail: alison.schecter{at}.mssm.edu.
Abbreviations:

r5gp120,

CCR5-specific gp120;

x4gp120,

CXCR4-specific gp120;

gp120,

glycoprotein gp120;

MAPK,

mitogen-activated protein kinase;

MIP-1,

macrophage inflammatory protein-1β;

PKC,

protein kinase C;

ROS,

reactive oxygen species;

SMC,

smooth muscle cells;

SDF-1,

stromal cell-derived growth factor-α;

TF,

tissue factor