SAN FRANCISCOWhen 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 40th 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.
