Body's proteins suppress AIDS virus.

After a frustrating, almost decade-long quest for HIV-fighting molecules naturally secreted by the body's immune cells, investigators have finally found a quartet of proteins that suppresses the replication of the deadly AIDS virus in infected cells. The discoveries represent a major development in AIDS research, offering the hope of novel therapies and clues to how some individuals successfully defend themselves for years against HIV's onslaught.

The search began in 1986, when Jay A. Levy of the University of California, San Francisco School of Medicine and his colleagues reported that a class of immune cells called CD8 can suppress the replication of HIV within nearby CD4 cells, the immune cells that the AIDS virus infects and uses to reproduce itself.

Levy and others quickly established that CD8 cells can secrete one or more soluble molecules that hinder HIV. Ever since, investigators have speculated that the factors may explain many long-term survivors, people infected with HIV who have not developed AIDS.

CD8 cells secrete only small quantities of the suppressive molecules, which makes it difficult to purify them. "The identity of the factor, or factors, has been elusive," says Bruce Walker of Massachusetts General Hospital in Boston.

In a report in the Dec. 7 Nature, a German group headed by Reinhard Kurth of the Paul Ehrlich Institute in Langen has now identified one of the elusive factors as interleukin-16 (IL-16), a little-studied protein that attracts CD4 cells. Three other small proteins, known to recruit immune cells for the inflammatory response, also impede HIV replication inside CD4 cells, further reports a group led by Robert C. Gallo and Paolo Lusso of the University of Maryland's Institute for Human Virology in Baltimore.

In work done at the National Cancer Institute in Bethesda, Md., Gallo and his coworkers modified CD8 cells to reproduce indefinitely. From these immortal cells, the researchers gathered enough secreted material to purify several proteins for testing. Three proteins-rantes, mip1-alpha, and mip1-beta-significantly thwart HIV's reproductive ability in laboratory cell cultures, the investigators will report in the Dec. 15 Science. Administered together, the three molecules stop HIV without harming infected cells, they say.

"When you add these factors, the virus shuts down," says Gallo colleague Anthony DeVico of Advanced Bioscience Laboratories in Kensington, Md.

Kurth's group uncovered IL-16's similar antiviral talents through studies of African green monkeys, which remain healthy despite infection by a simian equivalent of HIV. The investigators demonstrated that the monkey's IL-16 dramatically reduces the production of infectious HIV by infected cells. Human IL-16 also has antiviral properties, although possibly weaker, they report.

Neither group professes to know the exact mechanism by which the proteins suppress HIV, though both suggest that the molecules bind to CD4 cell surface molecules, sending into the cell's interior signals that halt virus replication.

The major issue provoked by identification of these molecules is whether their ability to suppress HIV production in test tubes reflects a natural antiviral role. "Does [viral suppression] actually occur in the body, and is it an important part of the body's defenses against HIV?" asks David Baltimore of the Massachusetts Institute of Technology.

Scientists now plan to test whether African green monkeys will develop AIDS-like symptoms if antibodies neutralize the protective proteins and whether the proteins stop HIV replication in other primates. They'll also examine concentrations of the proteins in human blood. "It would be exciting if long-term survivors have higher serum concentration than rapid progressors," says Kurth.

Walker cautions that the demonstrated viral suppression of the four proteins is weaker or, at best, only comparable to that of other potential AIDS drugs.

Furthermore, the discovered molecules are part of the intricate network of molecules, called cytokines, that immune cells use to communicate with each other. "It's going to be difficult to impact one cytokine without setting off a chain reaction of events," comments Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases in Bethesda, Md. Other interleukins have serious side effects or even kill when given at inappropriate doses, says Kurth.

Identifying these soluble HIV-suppressive factors "is very important and very interesting, but we've been down this road before, and it's a majestic leap from the test tube to the human body," concludes Fauci.