TURNING THE TABLES ON HIV

Although the research being done at the UCLA AIDS Institute will remain reso-
lutely focused on human retrovirus infections until the HIV pandemic is finally contained, the scientific breakthroughs achieved in our laboratories have implications—and applications—that are much broader. Indeed, work done
by Institute researchers to characterize, neutralize, and eradicate HIV have helped to propel advances in the understanding and treatment of diseases such as hepatitis B and C, influenza, and cancer.

In untreated mice with melanoma in their lungs (top panel, left image), the cancerous cells light up under a special imagining technique. When these same mice are injected with an untargeted vector, none of the vector finds its way to the cancer (top panel, right image). In healthy mice who receive the new treatment that Drs. Chen and Morizono have developed— an HIV-based vector that targets only melanoma cells—no response occurs, because there is no cancer for the vector to home in on (middle panel). But when mice with melanoma are given the vector, the overlap of cancer and vector is almost perfect (lower panel).

A dramatic recent example of how research on HIV can lead to potential treat-
ments for cancer has just been demonstrated by Drs. Irvin S.Y. Chen, the director of the AIDS Institute, and Koki Morizono. They are the first to show that an altered form of HIV—rendered harmless by the removal of roughly four-fifths of its genetic content—can be reprogrammed to hunt down cancer cells. If their work is confirmed by subsequent studies, this novel vector could be used to transport cancer-killing agents directly to tumors—an approach to therapy that would potentially eliminate many of the onerous side-effects that are associated with standard chemotherapy, because only tumor cells would be affected.

Previous attempts to turn the tables on HIV and other members of the retrovi-
rus family—by employing their extraordinary cell penetrating capacity to cure
rather than kill—have failed because researchers have tried to modify the outer envelope of those viruses. This modification renders the viruses harmless, but it also causes the envelope to become so deformed that it is no longer able to infect cells, according to Dr. Chen. To avert this inevitability Dr. Chen and his colleagues cloaked genetically-altered HIV with another virus, a modified form of sindbis, which typically infects insects and birds but poses no threat to humans. Masked by sindbis, genetically-modified HIV proved suffciently stable to serve as a cell-piercing carrier mechanism.

Drs. Chen and Morizono programmed their altered virus to attack and disable a protein, found on the surface of cancer cells, that ordinarily rebu1/2s anti-cancer agents. Although the specific target of this study was melanoma cells in the lungs of living mice, scientists could potentially use this carrier mechanism to target any protein on the surface of any cell. Indeed, the UCLA researchers have already found that their vector can pass the blood-brain barrier and enter the brain itself.

To demonstrate the effcacy of this homing device, Drs. Chen and Morizono tagged their carrier mechanism with luciferase, the protein that makes fireflies glow in the dark. Then then used a special camera, known as a “cooled charge coupled device,” to look for the glowing protein inside live mice. The stunning results of their experiments, which were recently published in Nature Medicine, are shown below.

Promising as this development is, it represents proof of concept, not a cure for solid-tumor cancers — not yet, anyway. “One of the problems with gene therapy,” Dr. Chen cautions, “is that the results of work like ours are so dramatic — in animal models—that it is hard to resist the impulse to try these new therapies out in patients. What experience has taught us is that premature trials in human beings can have tragic results, so we are not planning to move into clinical trials of our vector until the technique is fully refined.”