Camouflagingan impotent AIDS virus in new clothes enables it to hunt down metastasizedmelanoma cells in living mice, reports a UCLA AIDS Institute study in the Feb.13 online edition of Nature Medicine. The scientists added the protein thatmakes fireflies glow to the virus in order to track its journey from thebloodstream to new tumors in the animals' lungs.
"Forthe past 20 years, gene therapy has been hampered by the lack of a good carrierfor therapeutic genes that can travel through the blood and aim itself at aprecise location, thereby minimizing harmful side effects," said Irvin S.Y.Chen, director of the UCLA AIDS Institute. "Our approach proves that it ispossible to develop an effective carrier and reprogram it to target specificcells in the body."
TheUCLA team employed a two-step approach to transform HIV into a cancer-seekingmachine. First, the scientists used a version of HIV from which the viralpieces that cause AIDS had been removed. This allowed the virus to infect cellsand spread throughout the body without provoking disease.
"Thedisarmed AIDS virus acts like a Trojan horse —transporting therapeutic agents to a targeted part of the body, such as thelungs, where tumors often spread," said Chen, a professor of medicine,microbiology, immunology and molecular genetics and a member of the Jonsson Comprehensive Cancer Center at the David GeffenSchool of Medicine at UCLA.
Second,the scientists stripped off HIV's viral coat and re-dressed it in the outersuit of the Sindbis virus, which normally infectsinsects and birds. By altering the Sindbis coat, theyreprogrammed the AIDS virus, which ordinarily infects T-cells, to hunt down andattach to P‑glycoproteins — molecules located on thesurface of many cancer cells. The UCLA team is the first to prove that modifiedHIV will target and bind with P-glycoproteins.
"P-glycoproteins cause big problems by making the cellresistant to chemotherapy," Chen said. "They act like soccer goalies and punttherapeutic drugs out of the cancer cell. This prevents the drug from takingeffect and allows the tumor to continue growing unchecked."
Inorder to track the carrier's journey, the scientists added luciferase— the protein that makesfireflies glow —to the AIDS virus. They injected the camouflaged HIV into a vein in the mouse'stail and used a special optical camera to watch the carrier's movement.
"Thevirus traveled through the animal's bloodstream and homed straight to thecancer cells in the lungs, where the melanoma had migrated," Chen said.
Whenthe researchers held the mouse under the camera, the luciferaseilluminated the cancer cells, which glowed through the animal's bones, musclesand fur. The method is noninvasive and does not cause pain or harm to theanimal.
Thoughexcited at proving that HIV can be used to target cancer cells, Chen emphasizesthat the carrier must be further enhanced for safety and specificity before itcan be tested as a gene-therapy method in humans.
"Ournext step will be to test whether we can direct therapeutic genes to theprecise location where cancer cells reside," Chen said. "This approach offersmany potential applications for controlling cancer and other diseases."
"Wemay be able to boost immune-system surveillance at tumor sites, identify cancercells' exact location and kill them before they cause damage," he said. "Beyondcancer, it may be possible to correct acquired and genetic diseases where themutations exert their harmful effects on the body."
The National Institute ofAllergy and Infectious Diseases and National Cancer Institute funded the study.Kouki Morizono, Yiming Xie, Gene-Errol Ringpis, Mai Johnson, Hoorig Nassanian, Benur Lee and Lily Wuco-authored the research.