A Decoy for the Deadly AIDS

By Dick Thompson

Of all the drugs so far developed for AIDS patients, the one called CD4 is unique: it is the first substance designed specifically to combat the human immunodeficiency virus, which causes AIDS. A synthetic copy of a natural protein, CD4 prevents the deadly virus from entering and infecting healthy cells. While it cannot destroy the invader, scientists hope that CD4 can neutralize its ability to attack the human immune system. Says Samuel Broder, a National Cancer Institute researcher who is a leader in AIDS drug development: "It is one of the most important steps we have ever been able to take."

Last week the National Cancer Institute began testing CD4 in AIDS patients. ! The arrival of CD4, which had been previously tested in mice and monkeys, marks the beginning of a promising new era in drug development. Scientists have traditionally stumbled onto treatments by testing existing substances for their therapeutic effects, as was the case with AZT, the only AIDS drug approved for widespread use by the Food and Drug Administration. But recent advances in the field of molecular biology have given researchers a clearer understanding of the most minute workings of the cell. This has enabled them to engineer structures that can disrupt the cycle of a disease at the molecular level.

Developed by South San Francisco's Genentech, Inc., the CD4 currently in clinical trials is a copy of a protein that is anchored in the surface of cells known as T-4 lymphocytes. These cells are a pillar of the immune system and a key target for the AIDS virus. Natural CD4 attracts gp120, a molecule on the surface of the AIDS virus. In the usual course of the disease, the virus uses the natural CD4 to attach itself to a T-4 cell, which it invades and ultimately destroys. Synthetic CD4, however, acts as a decoy by latching onto the AIDS virus and rendering it incapable of binding to T-4 cells -- a process that a National Cancer Institute spokesman likens to "putting putty all over a porcupine."

AIDS sufferers and their support groups have reacted enthusiastically to CD4, but researchers strongly caution against premature euphoria. Says Ronald Mitsuyasu, associate director of UCLA's AIDS Clinical Research Center: "In the test tube, a lot of these drugs look like they inhibit the virus 100%, but when you use them on patients in a clinic it's a different story."

Although the tests on animals revealed no toxic effects, scientists point to possible complications involving the immune system. In a healthy individual, natural CD4 plays a regular role in fighting disease. It is unclear whether a flood of synthetic CD4 will interfere with that process. Another concern was raised by AIDS Researcher William Haseltine, of the Dana-Farber Cancer Institute, at the Fourth International Conference on AIDS in Stockholm last June. Haseltine suggested that an influx of CD4 could itself trigger an immune response in as many as 10% of those receiving the drug, causing them to develop antibodies against their own T-4 cells.

For all its promise, no one expects that CD4 will cure AIDS. Yet the drug is a potentially important new weapon in a growing arsenal of treatments. Researchers are learning how to use AZT more effectively to interrupt the virus' life cycle inside a cell. Probably the best hope for a successful AIDS treatment lies in a combination of these and other drugs.

With reporting by Scott Brown/Los Angeles and Jerome Cramer/Washington