mong the 50,000 to 100,000 genes enabling humans to function and reproduce are the genetic "switches" that regulate growth. Some of these switches "turn on" cell division and others turn it off, thus permitting individual organs to grow to the right size but no larger. The "oncogenes" stimulate cell proliferation and the "tumor-suppressor genes," or anti-oncogenes, shut down the process.
At ORNL researcher Craig Dees has become curious about the effects of a tumor-suppressor gene on the human immunodeficiency virus (HIV) that causes the acquired immuno-deficiency syndrome (AIDS).
In 1992 Dees and biologist Steve Foster, formerly with ORNL, showed that the ability of the AIDS virus to reproduce itself can be blocked by a gene product that suppresses the growth of cancerous tumors.
Dees and Foster demonstrated that the p53 tumor-suppressor gene can shut down, or "down regulate," the AIDS virus. For their research, they used a crippled AIDS virus that is unable to cause the deadly disease because it lacks genetic material that is normally "read" to produce the components of the AIDS virus.
The ORNL scientists found that the p53 protein may bind to part of the AIDS virus controller region, apparently interfering with its ability to stimulate production of genetic messages.
"The ability of the controller region of the AIDS virus to strongly stimulate genetic message production," says Dees, "helps the virus reproduce itself so very effectively." Thus, he added, interference with this process by p53 proteins might slow or stop duplication of the deadly virus.
Dees presented his results at the November 26, 1992, annual meeting of the Council of Animal Research Workers of America in Chicago, during a November 10, 1992, seminar at the University of Wisconsin-Madison, and at the 1993 AIDS symposium at Palm Springs, California.
The ORNL findings, Dees says, could have favorable implications for treating AIDS patients and people testing positive for HIV. "One remote possibility," he notes, "would be to remove a patient's bone marrow, genetically engineer the cells to produce large amounts of p53 protein, which might keep the AIDS virus under control, and reinfuse the treated marrow back into the patients. A more practical implication is that this new knowledge on how the virus controls itself could lead to development of new drugs to treat AIDS patients."
The ORNL scientists' original goal was to develop a new assay to screen chemicals for carcinogenicity. They theorized that many chemicals that stimulate uncontrolled cell growth may act by adversely affecting transcription, the process by which the genetic code is read and transcribed into a chemical message made of ribonucleic acid, known as messenger RNA. Messenger RNAs are read and translated into proteins that are used in the biochemical machinery or structural components of the cell.
Little is known about the complicated process of transcribing the genetic code into messages. The p53 protein is thought to be involved in this complex process. Viruses such as HIV insert themselves into the human genetic material and use the host cells' transcription machinery to duplicate themselves. The parts of the AIDS virus involved in stimulating transcription are many times more powerful than those found in a human cell.
"The AIDS virus has a very simple task, which is to make a large number of copies of itself," Dees says. "In the process of making more virus, the AIDS virus damages the human immune system, and other viruses, bacteria, or parasites combine to destroy our ability to defend ourselves. The virus apparently reproduces itself easily as a result of the powerful ability of its controller region to strongly stimulate transcription."
Because the transcriptional mechanisms of the AIDS virus are so potent, the ORNL scientists began using the AIDS virus' transcription system to study the effects of chemical carcinogens on transcriptional control, especially when the AIDS virus is combined with the p53 gene product. In the process, they discovered the ability of the p53 protein to limit transcription by the AIDS virus.
"Our current evidence," says Dees, "suggests that the p53 protein recognizes a specific genetic sequence within transcription-controlling regions of certain human genes and the AIDS virus. We think that p53 interacts with other cellular and perhaps viral proteins that bind to the controlling regions, turning down production of genetic messages.
"We also think that p53 acts in concert with other cellular transcription-controlling proteins to physically change the structure of the DNA, thereby making it less available to be transcribed. It seems that the key to curing AIDS is better understanding the molecular process of viral transcription and then rationally designing new drugs to suppress HIV transcription. Alternatively, we may be able to genetically engineer into the human immune system the ability to control the AIDS virus."