Two hoots to AIDS

A controversial marrow transplant operation in the US, a faulty gene in a dormant strain of the HIV isolated in Australia, the Zinc Finger factor ... the AIDS war is not lost yet, says SUNITA RAINA

Published: Thursday 15 February 1996

Two hoots to AIDS

-- (Credit: Shri Krishan)THE scene could be straight out of a medical sci-fi a baboon is sacrificed and its bone marrow processed; a person terminally ill - an AIDS (Acquired Immuno Deficiency Syndrome) victim who has volunteered to be a human guinea pig - is infused with about a pint of straw-coloured fluid containing baboon cells, which then flows from a plastic bag hung at the bedside, into a vein in the man's arm. The aim is to construct a parallel monkey-derived immune system in the man with in impaired immune response.

Yet, this was no medical fiction. The scene of this real life drama was one of the operation theatres in San Francisco General Hospital, USA. Meanwhile, there raged a stormy debate. The doctors concluding this highly risky operation were being castigated for violating medical ethics. The doctors had decided to go ahead on the face of warning from science advisors at the Food and Drug Administration (FDA) that it had greater chances of killing than benefiting the patient. But the patient had, in fact, campaigned for two years to be allowed to offer his services to science. And the controversy Would take a long time to die down.

"This represents not scientific progress but medicine and science gone mad," exclaimed experts in disgust. Chemotherapy, radiation and baboon cells involved in the transplant are likely to intensity the victim's infection by further weakening his damaged immune system, they held.

Prior to the bone marrow transplant, the patient underwent drug and radiation treatment to destroy virtually all of his already damaged immune system to prevent rejection of the transplant by the body. These exercises meant that the patient would surely die of AIDs-associated infections if the transplant failed.

"I know I could die from this treatment. But I am certain that I will die if I do nothing," said Jeff Getty, the test subject. He said that there are few treatments open to a late-Stage AIDS sufferer like him and he was putting his life on the line "to try to get some answers".

Nevertheless, scientists and medical ethicists have something else to say. They strongly feel that the test has slim possibility of helping AIDS Victims, on the contrary, scientists fear that the baboon transplant might carry known and unknown microbes that could go on to unleash a new epidemic like AIDS.

But Getty and his doctors went ahead with the experiment, nevertheless. The underlying principle of this novel experiment is deceptively simple, Baboons are resistant to AIDS virus. If everything goes as planned, the baboon cells injected into the patient's body will ride through his circulatory system to settle in his bone marrow. Once the baboon's immune cells take hold in Getty's body, they will perform the job that his AIDS-devastated immune system cannot.

The baboon marrow was processed to contain only two types of cells - stem cells that mature into key components of the immune system, and facilitator cells that allow stem cells to proliferate in other species without producing the fatal reaction called graft-versus- host reaction.

' If successful, the experiment shall boost animal-to-human transplants, known as xenotransplantation. The field is currently undergoing a revival of interest due to shortage of human organs and advances in immunology. There are critics, like Martin Stephers of the Humane Society in the US, who condemns xenotransplantation since "it does not balance the risk to the animal and the potential reward to humanity". it is feared that one such success, like this experiment, could open up the floodgates for a much gloomier scenario of assembly-line transplantation from animals to humans.

More good tidings
Apart from this controversial test, fight at the AIDS front in recent months has been greatly encouraging. Advances, though halting, reassure that AIDS might not be invincible after all- A major breakthrough was achieved when an Australian team cracked a mystery - a group of people who had contracted AIDS virus through transfusion 14 years ago, but were still healthy, all due to a faulty gene in the strain of virus which infected them.

"Not only have the recipients and the donor not progressed to disease for 15 years, the prediction is that they never will," marvels Australian molecular biologist Nicholas Deacon. "What these results suggest is that the human immuno deficiency virus (HIV) is vulnerable and that it is possible to stimulate effective immunity against it," says Barney Graham of Tennessee's Vanderbilt University in Australia.

Due to the presence of a defect in a gene - known as NEF, for negative factor, the virus is able to form very few copies of itself inside T cells, the immune system cells that the virus targets. Subsequently, a strong defence mounted by the immune system keeps the virus under control for many years. Scientists feel that the immune response launched thus may help prevent infection by more virulent strains of the AIDS virus.

This makes the NEF gene a promising target for drug developers. "If its activity can be blocked, researchers might be able to hold the progression of disease at bay, even in people who have developed full-blown AIDS," suggests Deacon. This bears significance in light of the fact that the powerful new generation Of AIDS drugs, called protease inhibitors, have sparked a debate vis-a-vis its efficacy. Some medical analysts are sceptical about the long-term value of this class of drugs, noting that the virus causing AIDS tends to mutate quickly. While the FDA approved two drugs in this class recently, named Saqumavir and Retanivar, it was unanimously felt that such drugs may need to be used in combination with other therapies.

The most coveted goal of AIDS drug research remains a hunt for the drug that solves the problem of drug resistance, while actually eliminating HIV from the body. Scientists made two significant advances in this direction in recent months. Since HIV mutates very fast, strains that resist a drug's toxic effects can evolve quickly. The immediate aim was to abort designs of the virus to develop drug resistance. Scientists recently celebrated the discovery of a family of drugs that do not allow evolution of drug-resistant mutant strains of viruses, including HIV.

By attacking the inner core of HIV called the Zinc Finger, Disulphide-substituted Benzamides (DIBAS) disable the virus to multiply. Zinc Finger is a protein containing a molecule of zinc that maintains a three dimensional structure of the virus. They have to stay the same if the virus has to multiply. DIBAS are found to remove zinc from the fingers disabling the virus (Down To Earth, Vol 4, No 16).

Researchers feel that this family of drugs may be a useful addition to the drug cocktail that might hold HIV in check indefinitely. "If Zinc Finger agents turn out to be as patent as these early experiments show, they might be very useful if we combine these with other drugs," says Clive Loveday, a virologist at Middlesex Hospital in London.

In addition, the first hints that it may be possible to eliminate HIV if the drug is given soon after the initial exposure sent the spirits of researchers seating. Since most HIV victims do not know exactly when they became infected, the discovery might at least save healthcare workers who fall in the clutches of the killer, accidentally.

A drug called PMPA was found to remove all traces of the simian immunodeficiency virus (SIV), which causes a disease Similar to AIDS in macaques. It was discovered that PMPA stays longer inside cells than zidovudine or AZT, the leading AIDS drug. Thus, it gets more time to combat the virus, eventually eliminating it completely. "It is some thing we have observed though we don't know why it happens," says Che-Chung Tsai at the University of Washington in Seattle. The snag remains that the drug has to be administered immediately after the virus gains entry into the body.

Medicine's holy grail
In fact, what scientists really want is a vaccine that call prevent infection altogether. That is what makes the virus strain discovered in Australia so promising, and controversial also. Could a weakened strain of the HIS, stripped of the NET gene, make development of the vaccine possible?

Ronald Desrosiers at the New England Regional Primate Research Centre provides hope. Ongoing work oil SIV has indicated that "when the NEF gene is removed from SIV, the virus has no longer the power to make monkeys sick. Moreover, monkeys inoculated with the NEF-free SIV developed marked resistance to the more virulent strain", recounts Desrosiers.

But testing a vaccine with live Irv, however weakened, on uninfected people sounds like walking over a landmine. After all, HIV is a retrovirus, a class of infectious agents known for their ability to integrate their genes into the DNA of the cells they infect. These can remain hidden for years, triggering the disease when the immune System falters.

The proposition of testing the live retroviral vaccine on perfectly healthy individuals, thus, does not muster much support. Nevertheless, sonic researchers do not want to write off a retroviral vaccine prematurely. "A live vaccine made from HIV can be made safer by removing not just the NEF gene but several others as well," maintains Desrosiers. Since the safety concern is overwhelming at present, most AIDS researchers argue that "the only prudent strategy is to concoct a hybrid vaccine, putting the key features of a disabled AIDS virus into something more benign than a retrovirus; like the vaccine virus that successfully wiped Out smallpox".

Till scientists find an answer to this dilemma, targeting the immune system rather than the virus seems a plausible alternative. Using natural substances produced by the human body to stimulate the immune system to fight the virus has attracted immunologists for long. The recent discovery of some such proteins created a buzz among researchers. interlelikin-16, a complex molecule isolated from the human immune system, was found to prevent the virus from replicating itself. Similarly, three chemicals - known as Ramcs, Nup I - alpha, and mipl-beti, also seem to block the progress of the disease.

Will these proteins in reality cure AIDS patients? Scientists are hopeful, yet cautious. Injecting these proteins directly into AIDS Victims is fraught with risks, feel researchers. "The chemicals may have other effects on the body, including potentially toxic effects, if given in large amounts, 11 cautions Bruce Walker of the AIDS Research Centre at the Massachusetts General Hospital, USA.

However, "from a conceptual standpoint the discovery is very important," says Anthony S Fauci of the National Institute of Allergy and Infectious Diseases in the us. The findings of these proteins have opened new pathways for AIDS research. Clues to various mysteries have been offered. Why does the virus never take hold in some people who are repeatedly exposed to it through risky behaviour? Why, even among infected people, some live into a second decade without succumbing to the disease while others fall ill within a few years Of HIV infection? Above all, the action of these immune system chemicals might solve the central mystery Of AIDS vaccine research- what reaction by the body must a vaccine elicit to protect against HIV infection?

The intense reactions to various approaches and findings reveal the extraordinary complexities of the AIDS research. Various strategies adopted by us to contain this most dangerous epidemic of the 20th century, like drugs, vaccines and immuno modulation, need further research. After all, we are dealing with chameleon of a virus that constantly changes tactics to counter our defences. But as researchers celebrate every advance they make at combating the deadly enemy, it becomes clear that AIDS may be anything but invincible.

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