HIV sexual spread exploits immune sentinels.

It's yet another illustration of the remarkable ability of the AIDS virus to exploit the immune system that seeks to destroy it. To find the so-called T cells that it most commonly infects, HIV seems to hitch a ride on specialized immune cells that patrol the body's mucus membranes, scientists report. These sentinels may also enable the virus to more easily infect its target cells.

This is the first time that biologists have shown that a virus takes advantage of one type of immune cell to infect another, says Yvette van Kooyk of the University Medical Center St. Radboud in Nijmegen, the Netherlands.

HIV's unwitting accomplices in this scenario are dendritic cells, immune cells that reside in the skin and the mucus-rich lining of parts of the body regularly exposed to foreign microbes. By displaying pieces of digested microbes, these crucial cells alert the rest of the immune system to infections.

Because T cells are rare in the vaginal and rectal mucosal surfaces, scientists have puzzled over how HIV is sexually transmitted. Dendritic cells may provide the answer. Scientists suspected that HIV initially infects dendritic cells, which would inadvertently distribute the virus when they rush to activate T cells in the body's lymph nodes.

The AIDS virus normally infects T cells by latching onto two types of surface proteins, CD4 and a class of molecules called chemokine receptors. In the new work, van Kooyk's team has identified another foothold for the virus, one specific to dendritic cells. Indeed, HIV attaches to this protein, dubbed DC-SIGN, more tightly than to CD4 and chemokine receptors.

"Amazing. [HIV] seems to be able to bind to molecules from three different receptor families. It is really clever and adaptable," marvels Edward A. Clark of the University of Washington in Seattle who studies dendritic cells.

The Dutch investigators unearthed DC-SIGN while studying how dendritic cells adhere to T cells in order to activate them. By isolating dendritic proteins that bind to T cells, they ultimately identified DC-SIGN as the key adhesion molecule.

The scientists learned that a research team had previously discovered this protein in 1992 because it binds to gp120, a component of HIV's outer surface. The team, however, did not determine what cell makes the protein.

The Dutch investigators, headed by van Kooyk and Carl G. Figdor, and AIDS researchers at New York University now report in the March 3 CELL that HIV uses its gp120 to bind to a dendritic cell's DC-SIGN. Moreover, they find that the bound HIV remains infectious for several days, easily long enough for dendritic cells to journey from the body's periphery to the lymph nodes.

They also find that when they mix HIV, dendritic cells, and T cells in a test tube, DC-SIGN somehow helps the virus infect T cells. Blocking the protein with antibodies slashes HIV's infectivity.

It's not clear whether HIV also exploits DC-SIGN to infect dendritic cells. Van Kooyk's group suggests that the virus may simply latch onto the protein and ride the immune cell like a cowboy on a bucking bronco until it brings HIV into contact with T cells.

Whether DC-SIGN leads to new AIDS drugs or vaccines may depend upon its role in the immune system. If antibodies or other drugs blocked the protein and thwarted HIV, would they impair the dendritic cells' responses against other microbes? "We need to know more about the biology of the molecule before we understand the range of therapeutic implications," says Clark.

Investigators plan to address that issue by giving antibodies that target DC-SIGN to primates and evaluating their health. They may also look among people for mutations in its gene. Some people, for example, have mutations in the gene for one of HIV's T-cell receptors. Unexpectedly, such people are healthy and resistant to both HIV infection and the development of AIDS.