When the AIDS-causing human immunodeficiency virus was discovered a decade ago, researchers were confident of finding a way to check its growth. Today, about 13 million people have been infected with HIV, but science is still groping in the dark for a cure for AIDS.
NEVER underestimate your enemy. But researchers trying to control the human immunodeficiency virus (HIV), which causes the Acquired Immuno-Deficiency Syndrome, or AIDS, overlooked this truism. In May 1983, when HIV was first discovered, cocksure boffins had announced they would conquer the most frightening scourge of the century in 2-3 years.
Ten years and billions of dollars later, there is no sign of the old euphoria. The researchers have been unable to find even a drug that can effectively check the spread of the virus, forget about a vaccine or cure. Meanwhile, HIV continues to take its toll. According to the World Health Organisation, about 13 million people have contracted HIV infection and this number may treble by the turn of the century.
In the absence of any drug or vaccine against HIV, AIDS has wreaked havoc in parts of Africa and threatens to overrun the fresh and immensely fertile territories of the developing world. Recent figures indicate that by the turn of the century, 95 per cent of HIV carriers will be in the developing world.
Little wonder, then, that uncertainty and pessimism marked the recently concluded Ninth International AIDS Conference in Berlin. The sombre mood at the conference, reflecting a decade of frustration and mounting tragedy, can be summed up thus: The more we learn, the less certain we are.
The success of HIV can be put down to its uncanny ability to mutate itself in response to an attack. Because its method of replication is so prone to error (its genes mutate a million times faster than human genes), it gives rise to extremely varied offspring, even within an individual host. Whenever a drug or immune response successfully attacks one variant of the virus, another arises to flourish in its place.
That, believe researchers, partly explains the various strains of HIV -- chiefly HIV-1 and HIV-2 -- found across the world. While some, such as HIV-1, are quite deadly, others may be relatively harmless. Still others undergo radical alteration and become undetectable. Some researchers believe these deadly-but-undetectable ones were probably behind last year's scare when some scientists, including Sudhir Gupta of the University Of California at Los Angeles, reported cases of people with an AIDS-like condition and yet not infected with HIV. The infection was suspected to be caused by a new AIDS virus.
The quick-change artistry of the AIDS virus makes it difficult to understand. Like all viruses, HIV is simply a strand of genetic material (in this case, the ribonucleic acid, or RNA) surrounded by a protein coat. A virus lacks the wherewithal to reproduce by itself, so it invades a living cell and takes over the host's molecular machinery. The intruder can then produce copies of itself, eventually killing the cell. One of HIV's favourite targets is the CD4 T-cell, which plays an important role in the human immune system.
But before a cure can be found for AIDS, there are several crucial questions that await answers: Why does HIV lie dormant in human cells, usually for years, before producing a full-blown case of AIDS? What triggers the deadly phase of the infection? How does the virus go about destroying the immune system? How does the body react to HIV assault?
Why the virus behaves the way it does is still a mystery. In the life cycle of ordinary viruses (in fact, in all living things), genetic information flows forward from DNA (deoxyribonucleic acid) to RNA to proteins. But HIV starts with RNA, goes backwards and generates its own DNA, then starts the forward journey by again producing RNA, followed finally by the production of proteins that go to make the fully developed virus. Because of this first backward step in their life cycle, this class of viruses has been called retroviruses.
Being a retrovirus, HIV is uniquely advantaged. After invading the body, it insinuates itself into the genetic material of the host. In this way, it is completely disguised and safe. In this dormant form, called provirus, it can persist in the body for a long time, in fact, until it gets an opportunity to make mischief.
The factors that trigger the dormant HIV into activity are called cofactors, but the search for them has been inconclusive. Several theories abound. Although the presence of genital sores from syphilis or other venereal diseases makes transmission of AIDS easier, neither the sores nor the microbes that cause them are necessary for HIV to spread.
Luc Montagnier, the French immunologist who discovered HIV causes AIDS and isolated the virus, believes the cofactor might be mycoplasma -- a primitive bacterium-like organism. He thinks it was a strain of mycoplasma that until recent years was confined to America. Somehow, somewhere, he conjectures, HIV and this cofactor got together in a group of humans, triggering the AIDS epidemic.
A little less mysterious than what activates HIV, perhaps, is the question of what causes the immune system collapse seen in AIDS. By now, it's well-known that HIV destroys CD4 cells, the superstars of the immune system. The greater the number of dead CD4 cells, the weaker the immune system becomes. Three explanations are offered, however, on how HIV bumps off these bodyguards. Firstly, HIV could kill them itself. Secondly, it may cause infected immune cells, such as killer T cells, to go berserk and attack healthy CD4s. Lastly, it may trick the immune system into attacking itself by mimicking parts of immune cell molecules.
A currently popular theory, propounded by Montagnier, suggests CD4 cells may be committing suicide under orders from HIV.
The infected immune system is like a person gone crazy. It must be subtly supported, nurtured, calmed down -- often all at the same time. To do that, scientists need to know how the body defends itself. But this knowledge, crucial to vaccine developers, is still to be coaxed out of the immune system.
Currently, the debate is over who does the defending, antibodies -- blood proteins produced to counteract foreign bodies or toxins -- or the killer T cells.
At the start of the quest for a vaccine, scientists focussed on simulating production of a specific type of antibodies, called neutralising antibodies, that bind themselves to the virus and prevent it from infecting cells. But neutralising antibodies are not the only knights-in-arms. The immune system has a "cell-mediated" arm that relies on the killer T cells to destroy virus-infected cells.
Things became more complicated as animal studies yielded ambiguous results. Curiously, while studies on chimpanzees elicited an antibody response, the immune system of monkeys seemed to favour the killer T cells.
It now seems, however, the chimp trials were loaded: The animals were exposed to small doses of virus just when their antibody levels were peaking. Also, no vaccine made from one viral strain protected a chimp from a different strain.
The protective role of neutralising bodies became even more suspect when Ronald Derosiers of Harvard's New England Regional Primate Research Center found a vaccine made from a live, weakened strain of SIV, HIV's simian cousin, failed to protect his monkeys from the virus even though it triggered a deluge of neutralising antibodies.
While Derosiers doesn't claim he knows precisely why his monkeys were protected, other researchers think his data suggests -- by elimination -- that cell-mediated immunity is the key to protection from HIV.
These researchers may be right, going by recent data from human studies. There is enough evidence to suggest that some infected people remain healthy because their cell-mediated immune response produces an as yet unidentified "soluble factor" that suppresses HIV replication.
Most researchers believe that "curing" HIV infection is an unrealistic goal. After all, they contend, HIV can insinuate itself into the host cell's DNA and remain dormant for a long time during which it is virtually undetectable. To truly cure AIDS, researchers would have to get rid of every infected cell, latent or otherwise, something which is currently unachievable.
The next best thing to do is to stop HIV from overrunning the host. For, so goes the argument, the fewer the number of viruses in the infected host, the less the damage.
But how HIV can be checked from spreading is again an open question. The HIV life cycle consists of more than a dozen stages and sabotaging any one could make the virus impotent. The trouble is that while many strategies can achieve this in a test-tube, success in the clinic has been long in the coming.
Until recently, most clinical successes have been achieved by stopping the viral genes from making reverse transcriptase, an enzyme critical to HIV's reproduction. All the licensed anti-HIV drugs -- AZT, ddI, and ddC -- attempt to cripple HIV here.
Other ways of curbing the spread of HIV are being studied. One promising target is an enzyme called the HIV protease, without which the virus gives rise to freaks that are non-infectious.
Other likely targets are HIV's regulatory proteins, which govern replication. One of them, called Tat, plays the midwife in the birth of a new virus from the inactive form of HIV DNA in the host's gene. A drug that could block Tat's action, could trip up viral replication.
But focussing on one or two viral proteins would be a mistake, believe some researchers. Malcolm Martin of the National Institute of Allergy and Infectious Diseases, USA, says the bottleneck in drug development is the lack of assays for screening drugs against specific viral targets. In some instances assays exist, but they aren't being used because researchers are concentrating on only a few targets.
If HIV were an ordinary virus, drug designers might have triumphed over it by now. "But it is a much more difficult virus than anyone anticipated," says Myron Essex of the Harvard AIDS Institute. "It has many more fancy genes to determine how it replicates. It has positive and negative controls that interact with cellular controls, which allows it to crank up rapidly or remain silent for a long time. It's a very, very unusual virus."
Most important, HIV can easily disguise itself by altering the proteins in its outer coat. When that happens, the job of finding and attacking the virus becomes harder. Even AZT, the main anti-HIV drug now in clinical use, is not as potent as doctors or patients hoped.
Approved five years ago in the US, AZT prevents one of the HIV genes from producing reverse transcriptase. In AIDS patients, the drug staves off death for maybe a year -- not exactly what one might call a cure.
The drug was also assumed to be helpful for infected but healthy people. But in April this year, an Anglo-French study called Concorde damned AZT as ineffective in slowing down the disease in this group. The only other anti-HIV drugs approved in the US -- ddI and ddC -- are simply variations on the AZT theme.
New strategies For many researchers, the Concorde results simply bolstered the belief that no drug by itself could knock out HIV. Therefore, researchers are now strafing HIV with several drugs at once, in the hope the virus may not be able to mutate fast enough to become resistant to a multi-drug combination.
By far the most famous, or rather infamous, multi-drug recipe is the one brewed by Yung Kang Chow, a medical student at the Massachusetts General Hospital, and his colleagues. The recipe was a combination of three drugs -- AZT, ddI and pyridinone -- that can disarm the virus of its crucial-to-life enzyme, reverse transcriptase. They found the combination forced HIV to "mutate itself to death."
But the road from the test-tube to the clinic is mined with uncertainties. Many treatments have shown great promise in laboratory experiments, only to prove ineffective or highly toxic when used on humans. But Chow's much-vaunted, media-hyped concoction, came to nought even before it could leave the laboratory when the researchers announced recently that their studies were fundamentally flawed.
Deciding which drugs to use together is a matter of trial-and-error, as there is no formula by which to prepare the most effective mix. So one begins by trying the shotgun approach: Select some promising drugs with few side-effects and throw them into the crucible. If you are lucky, the resulting compound might work.
The search for effective drugs is partly hampered by confusion over surrogate markers, which are indicators that tell researchers whether a treatment is actually preventing the progression of a disease or death.
The Concorde trial showed CD4 cells, surrogate markers in which people have reposed the most trust, do not necessarily measure the efficacy of a treatment. Spurred on by this, many researchers are looking again at a whole array of markers: for DNA and related chemicals, for viral proteins, for particular viruses and for various chemicals given off by an activated immune system.
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