Researchers Discover How Compounds Prevent Viruses From Entering Cells

The study, appearing in the September 11 Nature Immunology, alsoreceived funding from NIH's National Center for Research Resources.

"This discovery provides a basic understanding of a first-linedefense against such viruses as HIV and the influenza virus," saidDuane Alexander, M.D., Director of the NICHD. "This finding mayultimately lead to new strategies for preventing viral illness, and toincreased understanding of why some individuals are more resistant tocertain kinds of viral infection than are other individuals."

The means by which many viruses infect a cell is a two-stepprocess, said the study's senior author, Leonid V. Chernomordik, Ph.D.,Head of NICHD's Section on Membrane Biology in the Laboratory ofCellular and Molecular Biophysics. First, the membrane of the virus'outer coating, or envelope, must attach, or bind to, the outer membraneof the cell. After this attachment has taken place, the viral envelopemembrane combines with, or fuses to, the cell membrane. After the twomembranes have fused, the virus inserts its genetic material into thecell.

Defensins are produced by cells that are among the first tocome in contact with viruses, Dr. Chernomordik explained. Such cellsinclude leukocytes, a type of immune cell, and epithelial cells, whichline the surfaces of many organs and tissues.

In the current study, the researchers studied epithelial cellsfrom the inner surface of the lungs. The researchers discovered thatdefensins block the influenza virus entry into cells by preventing thefusion of viral and cell membranes. Specifically, the researchersstudied the antiviral effects of two different classes of defensins,theta-defensin and beta defensin.

Membranes--the outer covering of cells and of many kinds ofviruses--are coated with a layer of molecules called glycoproteins. Theglycoproteins protrude from the membranes' surface, in somewhat thesame way bristles stick out of a hairbrush.When the virus first infects the cell, glycoproteins on both the cellsurface and on the virus spread apart, as the viral membrane approachesthe cell membrane. To extend the hairbrush comparison, it's as if youcould slide the bristles to the side, and leave bare patches on eachhairbrush. At the bare patches, both the cell membrane and the viralenvelope come together, and membrane fusion takes place.

Defensins, the researchers discovered, bind crosswise toglycoproteins, preventing the viral and cell glycoproteins fromspreading apart. In keeping with the hairbrush comparison, it's as ifthe bristles of the hairbrushes were bound together with numerous smallrubber bands.

"Defensins do not kill the virus, they just prevent it from enteringthe cell," Dr. Chernomordik said. "Viruses that are not allowed toenter the cells can then be destroyed by the cells of the immunesystem."

Dr. Chernomordik and his colleagues also studied the activity ofmannan-binding lectin, a compound produced by the liver. Likedefensins, mannan-binding lectin also protects against viral infection.The researchers discovered that mannan-binding lectin prevents viralinfection in the same way that defensins do, by binding crosswise toglycoproteins.

Future studies of defensins may yield new strategies for preventingviral diseases, Dr. Chernomordik added. For example, by learning moreabout how defensins bind to glycoproteins, researchers one day may beable to devise new drugs that prevent viruses from entering cells.

Similarly, researchers might explore whether potential differences indefensin production might affect the ability to resist viral infection,Dr. Chernomordik theorized. For example, slight variations in the genesfor defensins might make the molecules either more, or less, effective,at combating viruses. Similarly, some individuals may produce moredefensins than do others.

Other authors of the paper were Eugenia Leikina, Helene Delanoe-Ayari,Kamran Melikov, and Andrew Chen of the NICHD; Myoung-Soon Cho, of theNHLBI; and Alan J. Waring, Wei Wang, Yongming Xie, Joseph A. Loo andRobert I. Lehrer of the University of California at Los Angeles.

The NICHD is part of the National Institutes of Health (NIH),the biomedical research arm of the federal government. NIH is an agencyof the U.S. Department of Health and Human Services. The NICHD sponsorsresearch on development, before and after birth; maternal, child, andfamily health; reproductive biology and population issues; and medicalrehabilitation