French Researchers Discover How HIV Makes First Contact

SAN FRANCISCO—When the HIV virus is acquired through breast-feeding or sexual activity, its first contact is with the epithelial cells of the gastrointestinal, anorectal, or genitourinary tracts. It then appears to use a raft mechanism and transcytosis to pass through the epithelial cells to enter and infect the submucosal target cells, French researchers said at the 40^th Annual Meeting of the American Society for Cell Biology.

Morgane Bomsel, PhD, research director, Centre National de la Recherche Scientifique (CNRS), working in the Institut Cochin de Genetique Moleculaire, Paris, and her colleagues have shown that to enter epithelial cells, HIV cells use envelope glycoprotein subunits gp-120 and gp-41 to bind to galactosyl ceramide, a glycolipid receptor at the epithelial cell surface.

HIV passes through the epithelial cells without actually infecting them. To do this, the virus uses a normal pathway called transcytosis. During transcytosis, proteins or particles are taken into vesicles in the epithelial cell, ferried through the cell, and released on the other side into the host’s submucosal mononucleated target cells. The entire process takes about 30 minutes.

The researchers suspected that to transport HIV, the epithelial cells needed a stiff raft-like portion. To test this theory, they put cholesterol-removing chemicals in sample epithelial cells. Since cholesterol hardens membranes, the chemicals would eliminate the ability of the cell to form the raft portion. Indeed, when these cells were then exposed to HIV, the epithelial cells did not attach to or transport the virus.

Transcytosis of HIV was also blocked by treatments that disrupted the lipid composition of galactosyl ceramide. "The structure of this peptide is very important to the transport of HIV," Dr. Bomsel said. HIV transcytosis thus depends on the membrane organization of raft microdomains in epithelial cells that are stabilized by cholesterol, she concluded.

The researchers believe they may have found a way to block the transcytosis of HIV and keep the virus from infecting healthy cells, using treatments that block the action of the virus with galactosyl ceramide at the epithelial cell surface.

They have discovered an antibody secreted in human mucosa that binds specifically to a region in one of the HIV envelope subunits that bind to galactosyl ceramide. "These antibodies, which are present in the mucosa of HIV patients, neutralize the transport of HIV at the epithelial cell surface," Dr. Bomsel said.

To be effective, such antibodies would have to be manufactured in much larger quantities than normally present in the average person’s mucosa. "We’re not sure exactly yet how to raise the levels of these antibodies in vitro, but we are currently working on it," she said. Annette Alfsen, MD, PhD, also of CNRS, was co-author of the paper.