The New York Times - December 24, 1985
Harold M. Schmeck Jr.

Rock Hudson's recent death after a futile trip to Europe for treatment with a drug called HPA-23 and the French announcement that cyclosporine looked hopeful against acquired immune deficiency syndrome after brief use in a few patients received huge publicity. Both drugs are still being tested but the incidents only underscored the fact that as yet no effective treatment exists anywhere.

Meanwhile, with little fanfare, scientists have found several drugs that are active against the AIDS virus in the test tube and have identified chinks in the virus' armor that appear worth pursuing in future drug design. The new clues are being followed urgently but with the knowledge that there is a long, immensely difficult, road ahead.

The reasons for urgency are obvious. Today there is no preventive vaccine and no cure once the disease begins. There is not even any drug that can be depended on to modify the course of the illness.

But drugs effective against any viruses have long been among the most difficult goals of medical research. While hundreds of different medicines have been developed to treat bacterial infections, there are only a handful that can cope with any virus diseases.

Smallpox, the only major virus that has been eradicated, and several others such as polio and measles that have been largely conquered have all been defeated by vaccines. The effort to develop a vaccine against AIDS also has a high priority today. But Government experts do not expect a vaccine or any treatment to halt spread of the virus to be generally available before 1990.

Meanwhile, the number of AIDS cases in the United States is aready over 15,000 and is increasing rapidly. The National Institutes of Health are recruiting medical centers throughout the country to carry out early human trials of promising new drugs. Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, one of the institutes, has estimated that as many as 2,000 patients might be involved in such trials by the end of next year. A program sponsored by the National Cancer Institute has tested about 150 compounds in the laboratory, according to Dr. Samuel Broder, who heads a drug evaluation committee of the institutes.

"I think the whole issue of chemotherapy for viruses poses a formidible challenge no matter what virus you are talking about," Dr. Broder said, but he added that the wealth of new information that is coming to light on viruses keeps him from being discouraged.

The search for substances to fight the AIDS infection provides the most dramatic illustration of the problems and possibilities of all antiviral drug research. At least eight experimental drugs have already shown some ac tivity against the AIDS virus, which has been given different names by different research groups: HTLV-III, LAV and ARV. Some of the drugs are already being tried in a few patients.

But nobody underestimates the gravity of the problems ahead.

Viruses are far smaller and simpler than bacteria and can reproduce only by invading living cells. While this might seem to make viruses more vulnerable to attack by drugs, the truth is just the opposite. Most chemicals that would kill the virus will also kill the cells they infect because the life processes of virus and cell become so closely linked.

"The main thing is that bacteria grow outside of cells and have very different enzymes and replicative mechanisms," said Dr, Martin S. Hirsch of Massachusetts General Hospital and Harvard University. "Viruses grow exclusively within cells and take over the cells' machinery." Antivirus drugs therefore have to seek targets that are unique to the virus; otherwise the cells of the patient's body will be poisoned by the same chemical sent in to poison the virus.

Viral Infection Process

The general sequence of events in a virus infection has long been known.

Virus particles consist of pieces of genetic material, either DNA or RNA, wrapped in coats of protein. At the start of a typical infection, the virus particle homes in on a susceptible cell, attaches to its surface and manages to insert its genetic material inside. The alien virus genes then subvert the cell's own genetic instructions and force the cell to produce a new crop of virus particles that emerge to infect other cells, often killing the original cell.

The intimacy of the relationship between virus and infected cell in this process of subversion explains why it is so difficult to find chemicals that will kill the virus without killing the cells. In recent years, however, much has been learned about the finest details of the subversion and some of this knowledge has suggested specific targets for attack against the virus. Against some viruses this new wealth of knowledge has already paid off. #3 Virus-Fighting Drugs Dr. Hirsch cites three drugs in particular as valuable against some important viruses other than that of AIDS: amantadine, which is considered useful in preventing and treating the viruses that cause influenza A; vidabarine and acyclovir, both of which are active against various forms of herpes infection. He notes that there are several other potentially important new antivirus drugs that may broaden the attack to include some other important viruses.

The American Medical Association's compendium titled "A.M.A. Drug Evaluations" has a similar list of useful antiviral drugs, but notes that there have been relatively few important advances in the drug treatment of virus infections.

Amantadine, the first of the modern antiviral drugs, is believed to act by disrupting the process by which the virus sheds its protein coat early in its invasion of a cell. Vidabarine and acyclovir interfere with enzymes necessary to the virus. These enzymes are sufficiently different from native enzymes of the cell so that they might be attacked without major damage to the patient.

Another strategy is to interfere with receptors on the cell surface to which the virus attaches. Still another is to disrupt the process of final assembly of new virus particles.

Until recently many of the specifics of these steps in virus infection had not been understood in great enough chemical detail to be exploited. The rapid advances made in recent years by molecular biologists have been changing that picture for the better.

A Difficult Task

The search for chinks in the armor of the AIDS virus has been helped by this explosion in knowledge, but the more scientists learn about the virus, the more difficult it appears to be.

In one respect, the peculiar nature of the virus itself may be a hopeful clue. The virus of AIDS is of a special kind called a retrovirus. These viruses offer one special point of attack that other viruses lack. The meaning of the name retrovirus itself explains this.

When any living cell uses its store of genetic information, the normal sequence of events is to copy the message encoded in its DNA into the form of RNA, which then becomes the blueprint for making a needed protein. Retroviruses reverse this process. Their core of genetic material is RNA. The viruses use a special enzyme called a reverse transcriptase to translate the message of the virus' RNA into the form of DNA. Human cells have no reverse transcriptase enzymes. If drugs can be developed that inactivate that enzyme, they should halt the virus infection.

Dr. Hirsch, who has been involved in antiviral drug research for 15 years, said he knows of at least eight experimental drugs that today show activity against the AIDS virus in the test tube and five of these act against the reverse transcriptase enzyme.

Dr. Broder of the National Cancer Institute, who heads a National Institutes of Health panel to evaluate AIDS drugs, said he too likes the strategy of attacking the reverse transcriptase enzyme. Several drugs are undergoing early tests in humans in this country and two of them, suramin and azidothhymidine, are known to act against the enzyme. In theory it should be possible to attack the reverse transcriptase without harming the patient's cells, but, in fact, some of the anti-reverse transcriptase drugs have been found toxic.

New Experimental Drug

Recently scientists of the cancer institute, Yale, the University of Florida and a commercial company, Matrix Research Laboratories, described a new drug, AL 721, which can halt AIDS virus infection of blood cells in the laboratory. It is believed to act not against the reverse transcriptase but by disrupting the virus' protein coat. The scientists caution, however, that much more work will be needed to tell whether or not it has any value against AIDS.

Another drug that is now being tried in a few AIDS patients is ribavirin, a compound, which has already been reported to have value in treating patients who suffer from any of several other virus diseases. Its mode of action against viruses is not entirely understood. It may act differently against different viruses.

Yet another possible way of attacking the virus has been found recently. Dr. William Haseltine and colleagues at Harvard, discovered that the AIDS virus has a special gene that is vital to its ability to subvert cells. The scientists have named the gene TAT for transactivating transcriptional gene. It is possible that drugs might be developed to interfere with that gene or its product.

Natural substances such as interleukin 2, the interferons and other stimulants or products of the immune defense system can now be made in large quantity by gene-splicing methods. These are being considered for use against AIDS in conjunction with antiviral drugs. Early tests of the immune defense stimulants alone did not show much promise. But coupled with a virus killing drug, such substances might prove useful, some scientists believe.

Viral Invasion of Brain

Within roughly the past year it has become clear that the AIDS virus invades the brain as well as cells of the immune defense system. This discovery has been bad news not only for the individual patients, but also for the prospects of successful drug treatment. A biochemical barrier called the blood brain barrier keeps many substances, including many drugs, out of the brain. This, in turn makes the brain and central nervous system a sanctuary for the AIDS virus.

Some antiviral drugs pass through the barrier. Others do not, but much current research is aimed at means of carrying drugs across the barrier. Scientists of a Florida based company called Pharmatec, collaborating with academic researchers have reported some promise in this work.

Given the emerging importance of the brain as a sanctuary for the AIDS virus, Dr. Broder said he would not be enthusiastic about any drug that could not reach the brain.

Another fundamental problem in drug attack against AIDS is that the virus' genetic information becomes incorporated into that of the cells that are infected and may remain there indefinitely in a dormant or latent state. Later the viruses may emerge again in a cell-killing rampage. But while in the latent state, the viruses are virtually impossible to attack.

A consequence of this is that any future drug to combat AIDS might have to be given periodically, perhaps for the lifetime of the patient.

Everything that has been learned to date, Dr. Broder said, shows that AIDS is a most difficult problem. Even if a drug proves active in laboratory tests, he said, that is no proof that it will be useful at all in patients. But, like many other scientists, Dr. Broder sees no reason for despair and many reasons, all based on the new fruits of research, to continue to hope and to work.

851224
NYT851232