Blocking an enzyme prevents HIV infection.

In an unusual twist to the understanding of how HIV infection occurs, researchers at Boston University School of Medicine have discovered that an enzyme found on the surface of some cells breaks certain chemical bonds in the AIDS-causing virus' outer coat. This sets off a chain of events that enables the virus to enter the cell.

Inhibiting this enzyme -- protein disulfide-isomerase, or PDI -- prevents HIV from infecting cells grown in the laboratory, Hugues J.-P. Ryser and his colleagues report in the May 10 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES.

Since 1984, scientists have known that HIV binds to the CD4 protein found on the surfaces of some immune cells. However, binding to the CD4 receptor isn't sufficient to trigger infection. Some cells that carry CD4 and bind to the virus remain resistant to HIV. Ryser believes he has found a second factor necessary for HIV infection. By breaking the disulfide bonds that help form the shape of HIV's surface, he suggests, PDI allows the virus to fuse with the cell membrane.

"[Ryser's work] is intriguing," says pathologist Jonathan Braun of the University of California, Los Angeles, School of Medicine. "It's certainly a plausible and somewhat functionally defined mechanism for HIV entrance into the cell."

Ryser's team inhibited the effects of PDI by using three different classes of drugs. One, a nonspecific agent called DTNB, blocks all enzymes at the cell surface, including PDI, that contain a hydrogen-sulfur group. The other two, the antibiotic bacitracin and antibodies against PDI, specifically inhibit PDI's activity. All prevented HIV infection of cells but did not affect the replication of HIV in previously infected cells.

Few researchers have investigated the first steps of HIV infection, says Ryser, especially since the disulfide bonds in HIV were thought to be inaccessible to enzymes.

PDI is normally found inside cells and has only recently been shown to exist on the surface of some. Most anti-HIV drugs have tried to stop replication of the virus inside the cell, Ryser adds. He believes his work suggests promising new targets for therapeutic intervention.

Other scientists are not so sanguine, since many drugs that have blocked HIV in laboratory tests have not proved as successful in people.

This research may have implications beyond preventing HIV infection, says Dennis T. Brown, a molecular biologist at the University of Texas at Austin who has studied the Sindbis virus. This virus normally does not affect humans but can be deadly when it does. The same chemicals that block HIV's entry into the cell block the Sindbis virus, he says.

PDI's role in breaking viral disulfide bonds, Brown adds, "may be an emerging motif for many viruses that enter cell membrances by cell fusion."

His work may be unexpected, says Ryser, "[but] I'm very eager to see other people look into the implications. After all, we have a big problem on our hands with AIDS and every avenue should be explored. This is a very intriguing and unusual avenue."