The human immunodeficiency virus (HIV) is pretty remarkable in its ability to spread throughout the body and, as a retrovirus, to rewrite the DNA of the cells it attacks. But the part of the virus genome which makes it so prolific is not the same part which triggers such a deadly disease. It is possible, in fact, to remove the disease-causing payload of HIV entirely, creating an "impotent" strain of the virus. As will be reported in the upcoming edition of Nature Medicine (abstract online), such a neutered form of HIV has been used by a UCLA research team to target melanoma cells in mice -- in effect, to lay the groundwork to use HIV to fight cancer.
The UCLA team employed a two-step approach to transform HIV into a cancer-seeking machine. First, the scientists used a version of HIV from which the viral pieces that cause AIDS had been removed. This allowed the virus to infect cells and spread throughout the body without provoking disease.
"The disarmed AIDS virus acts like a Trojan horse – transporting therapeutic agents to a targeted part of the body, such as the lungs, where tumors often spread," said Chen [Irvin S.Y. Chen, Ph.D., director of the UCLA AIDS Institute], a professor of medicine, microbiology, immunology and molecular genetics and a member of the Jonsson Comprehensive Cancer Center at the David Geffen School of Medicine at UCLA.
Second, the scientists stripped off HIV's viral coat and redressed it in the outer suit of the Sindbis virus, which normally infects insects and birds. By altering the Sindbis coat, they reprogrammed the AIDS virus, which ordinarily infects T-cells, to hunt down and attach to P-glycoproteins -- molecules located on the surface of many cancer cells. The UCLA team is the first to prove that modified HIV will target and bind with P-glycoproteins.
"P-glycoproteins cause big problems by making the cell resistant to chemotherapy," said Chen. "They act like soccer goalies and punt therapeutic drugs out of the cancer cell. This prevents the drug from taking effect and allows the tumor to continue growing unchecked."
They also added the DNA for luciferase, the protein which makes fireflies glow, in order to be able to track the HIV throughout the mouse body. The targeted HIV went right to the melanoma, which had moved to the mouse's lungs.
The next step will be to replace the HIV "payload" with a cancer-fighting gene; the technique may also be useful more broadly for genetic therapy. Wired News notes that Chen and the UCLA team are cautious about the process, however.
More incremental work, with the goal of increasing the precision of the treatment and reducing the chance of side effects, is necessary before this type of gene therapy can be tested in humans, Chen said. In a premature human trial in 1999, 18-year-old Jesse Gelsinger died during a gene therapy clinical trial at the University of Pennsylvania, which led to an FDA investigation and closure of the Penn gene therapy program.
"I think one of the problems with gene therapy has been whenever people get a new approach they immediately go into patients," Chen said. "Our approach has been test in cell culture, then in mice. We're not planning any clinical trials until this is fully refined."
Additional details can be found in the BBC News story.