The nine genes from hell Viruses are tiny , which is one reason that they need so much help reproducing . Most viruses are made of DNA ( their genes ) and protein . Yet both sorts of drug share the same underlying concept - - they jam the function of a crucial enzyme . Most viruses evolve by one mutation at a time - - it is not easy for them to exchange genes , as many living organisms do , by having any form of sex .

A new class of drugs has brought the possibility that AIDS may now be a treatable disease . BATTER hard enough at something and you may just break through . That is what many of the world 's AIDS researchers now believe they have done . After spending billions of dollars and marching up numerous blind alleys , they have developed a treatment that appears , on the basis of preliminary trials , to be able to put patients into remission . This means that their bodies can keep the human immunodeficiency virus ( HIV ) , the agent that causes the disease , at such low levels that it appears to do no harm .

Unlike existing medicines for AIDS , the new treatment does not merely postpone death , it restores vitality . It may even , according to a few of its strongest partisans , be able to clear HIV completely out of a person 's system , thus effecting a cure . It is known as triple - drug therapy and it relies on mixing the therapeutic advantages of older medicines , such as AZT , with those of new ones - - called protease inhibitors - - that attack a different part of the viral life - cycle .

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The immune system , the organ assaulted by HIV , is one of the most complicated in the body . Unlike most organs , it is not confined to a single place - - the infections it has to deal with can , after all , develop anywhere . Its cells ( known as lymphocytes ) grow and mature in bone marrow , and in a gland known as the thymus . They then spend their time commuting via the bloodstream between various depots , such as the lymph nodes , that are scattered around the body . This ubiquity makes the immune system easy to overlook . But it is a big organ . Its cells , collectively , weigh as much as the brain or the liver , and represent an enormous physiological investment .

Such a huge mass of tissue is bound to attract parasites . Viruses , such as >HIV, are the largest class of parasite around . Being little more than gift - wrapped genes , they are incapable of reproducing themselves without a serious amount of help . The help is provided ( involuntarily ) by cells in the body of the creature that the virus has invaded .

Viruses are usually specialists , and HIV specialises in a type of lymphocyte known as a helper T - cell . The role of helper T - cells is to encourage the front line of the body 's defence system , such as the cells that make antibodies and the cells that help control bacterial and fungal infections , to respond . Take these defences away and the immune system collapses . Infectious diseases that the body would normally shrug off become lethal , and the patient has AIDS .

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The nine genes from hell Viruses are tiny , which is one reason that they need so much help reproducing . They are composed of but a few hundred molecules . Most viruses are made of DNA ( their genes ) and protein . HIV , however , belongs to a rareish class known as the retroviruses . Instead of DNA , the genes of a retrovirus are made of its chemical cousin , RNA. HIV 's RNA carries nine genes - - each the blueprint for one or more of the types of protein needed to make new viruses . These proteins are the chemicals that do the donkey work of getting the virus into a cell and then persuading that cell to manufacture new proteins ( and new RNA ) using the genetic blueprints on the old RNA .

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Anti - viral drugs , such as those in the newly developed cocktails , are designed to throw spanners into the reproductive works . The idea is to upset the viral production line while doing as little damage as possible to the patient . The more spanners that are thrown , the more successful the exercise is likely to be .

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The old spanners , drugs such as AZT , delay death , but often not for long . They interfere with the defining peculiarity of retroviruses - - which is that , in order to get a host cell to pay attention to them , they must copy their RNA into DNA ( the usual currency in which genes are stored ) and then smuggle it into the host cell 's nucleus , where it can hide among the host genes and manipulate the cell 's operations . Stop this " reverse transcription " ( of RNA into DNA ) , and you stop the virus .

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The new drugs , by contrast , clobber the virus after this , at the point where it sticks its nose out of its host 's nucleus and gets the cell 's machinery to start churning out new viral proteins . Yet both sorts of drug share the same underlying concept - - they jam the function of a crucial enzyme . AZT and its kin work by jamming reverse transcriptase . This protein converts the RNA into DNA in preparation for its integration into the cell 's nucleus by a second enzyme , integrase . The new drugs block the activity of HIV protease , a further enzyme which is needed to take the products of two of the largest viral genes ( known as gag and pol ) and break them up into useful proteins . The fragments this protease carves from the raw material that gag and pol provide include reverse transcriptase , integrase , and protease itself , as well as several of the proteins that form the " body " of the virus . No protease , then , means no infectious virus .

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Blocking the action of HIV 's protease ( and , indeed , of its reverse transcriptase ) is done with geometry . All enzymes possess an active site within the folds of their atoms . This is where the chemical reaction that they assist ( which usually involves either joining two things together , or breaking one thing apart ) takes place . The active site is exquisitely tailored to accommodate the molecule or molecules that it is designed to operate on . An analogy often used is that of a lock that will accept only the correctly shaped key . But most locks will also accept a key that is not quite the right shape . Until , that is , the key is turned . Then they jam .

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Protease blockers ( like reverse transcriptase inhibitors ) are the wrong - shaped keys . The three that have already received the blessing of America 's Food and Drug Administration are saquinavir , which is produced under the trade name " Invirase " , by Hoffman - La Roche ; ritonavir ( " Norvir " ) , manufactured by Abbott Laboratories ; and indinavir ( " Crixivan " ) , made by Merck . And at least four other compounds are currently undergoing tests .

The more potent of these protease blockers - - ritonavir and indinavir - - are about 100 times as effective at wrecking HIV 's reproduction as is AZT. This , however , is still not enough . The real trick is to combine them with reverse - transcriptase blockers .

Darwinian molecules The conceptual breakthrough that led to this idea was published early in 1995, by David Ho , of the Aaron Diamond AIDS Research Centre in New York , and George Shaw , of the University of Alabama at Birmingham , in a pair of papers that revolutionised people 's views of AIDS .

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One of the puzzles of the disease was the long period that can elapse between someone 's picking up the virus and their going on to develop the symptoms of the disease . The prevailing idea had been that , after an initial burst of activity , HIV became dormant . It hid somewhere in the body , often for years , and then , for some unknown reason , broke out . For this reason , AZT and its cousins ( all of which have unpleasant side - effects ) were reserved for use when symptoms actually appeared - - which was part of the reason that they proved ineffective .

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Dr Ho and Dr Shaw demonstrated that this theory was wrong . By applying existing protease inhibitors , they showed that the virus continues to multiply throughout the latent period , but is kept in check by the immune system . This blocking task is enormous . As many as 10 billion virus particles may be generated in a carrier 's body each day . This means that almost every conceivable mutation of the virus 's nine genes is likely to occur roughly once a day . As the virus multiplies , these mutants undergo intense natural selection in their conflict with the host 's immune system . Eventually , a strain arises that can beat it . The host 's T - cells are killed faster than they can regenerate . And he develops AIDS .

Enzyme - blocking drugs add an extra layer of defence . They compel the virus to find , through natural selection , some form that can beat the drug as well as the immune system . But the principle is the same . Sooner or later an enzyme will emerge that is the right shape to do its job , but the wrong shape for the drug to fit in and jam . The virus ( or , at least , the strain of it carrying this modified enzyme ) is now resistant to the drug .

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Confronted with three drugs , working in two completely different ways , however , natural selection cannot cope . Most viruses evolve by one mutation at a time - - it is not easy for them to exchange genes , as many living organisms do , by having any form of sex . To beat the multi - drug therapies , several beneficial ( to the virus ) mutations need to be present at the same time . Coincidences are possible ; therapies that can be overcome by two or three simultaneous mutations might still be beaten . But the triple - drug therapies now on offer require somewhere between six and nine beneficial mutations to occur at the same time if they are to be beaten - - a risk against which the odds are long , even when the body is producing 10 billion virus particles a day .

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However , the added beauty of triple - drug therapy is that the body very rapidly stops producing virus particles at this rate . Protease blockers , even when they are administered alone , can reduce the rate at which the virus is multiplying by as much as a hundred - fold . This rapidly lengthens the odds of parallel , beneficial , mutations arising . The rarer the virus , the less the chance of such a combination of mutations arising by chance .

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And the rarer the virus , the longer the patient will live . Indeed , the best predictor of how long someone who has been infected with HIV will survive seems to be the amount of virus in his blood - stream . This can be measured , approximately , by counting the number of copies of viral RNA per millilitre of blood using a test such as the polymerase chain reaction ( PCR ) .

That virus levels are linked to lifespan may seem obvious , but until recently it was not . Doctors used to arrive at a patient 's prognosis by counting his T - cells , on the not unreasonable assumption that it is a lack of T - cells that causes AIDS . But a long - term study published in March , by John Mellors and his team at the University of Pittsburgh , suggests that examining viral loads can predict lifespan up to ten years into the future , something that T - cell counts are much less capable of doing . Dr Mellors found that patients with fewer than 5,300 RNA strands per millilitre of blood in 1985 had a 38% chance of dying within a decade . Those with more than 37,000 per millilitre were exactly twice as likely to succumb . So measures that bring down the viral load might be expected to have a good chance of prolonging life .

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Three 's company This is just what triple - drug therapy does . The focused triple - drug trials that have been reported so far have been carried out on relatively small numbers of subjects ( the drug companies ' original trials of their protease blockers , though carried out on larger groups , did not concentrate on triple therapies ) . But the results are still impressive .

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Roy Gulick , of New York University , supervised a study of 97 people who are being treated with indinavir , AZT and 3TC ( another reverse - transcriptase blocker ) . Although only the first six months ' worth of data have been analysed ( a full year 's worth of figures will be released in July at the International Conference on AIDS in Vancouver ) , this work has already caused astonishment amongst AIDS researchers .

Many of the participants had advanced AIDS . Their RNA counts were over 40,000 copies per millilitre and their T - cell counts were falling . The treatment ( which amounted to 20 pills a day ) reduced the virus level in the bloodstream of 90% of them to a point where it could not be counted by PCR. Perhaps more important than that , the patients in this trial have become visibly better . They are putting on weight and shaking off the opportunistic diseases that batten on to sufferers from AIDS and eventually kill them .

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Dr Ho and Martin Markowitz ( also at the Aaron Diamond Centre ) are conducting a triple - therapy trial in people at the other end of the HIV spectrum - - those newly infected with the virus . So far , they have enrolled 18 people in their study - - the first joined up ten months ago . These people take about three months to become clear of the virus when treated with indinavir or ritonavir along with AZT and 3TC .

Larger triple - drug trials are now in progress . The AIDS Clinical Trial Group , a government research programme based in Washington , DC , is supervising one that involves 1,750 people . And Hoffman - La Roche and Abbott are extending the idea of multiple - therapies by combining their two protease inhibitors in one of them .

The drugs , of course , are not perfect . One of the main obstacles is that they are very expensive . They can take as many as 16 chemical steps to manufacture . Partly as a result , a year 's course of triple - drug therapy is reckoned to cost something like $10,000 - 12,000. At this price it will be of precious little use to more than 90% of those people infected with the virus - - the ones who live in poor countries .

There are also questions over what is known as the " bioavailability " of one of the drugs - - saquinavir . It is one thing for something to work in a test tube ; quite another for it to be able to move from the stomach to infected T - cells , and still be active . Much of Merck 's research effort was directed towards pulling off this trick . One of the reasons for Hoffman - La Roche 's collaboration with Abbott is that saquinavir 's activity is massively boosted in the presence of ritonavir . And a third caveat is that although the ability of the drugs to clear away the virus and restore everyday health is impressive , the actual increase in patients ' T - cell counts is not , so far , that much better than that achieved with reverse - transcriptase inhibitors alone .

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Nor is it clear whether a patient can ever stop taking the drugs and be pronounced properly better . Despite the billions that have been spent on studying it , many aspects of AIDS are still mysterious . HIV is able to effect its entry into T - cells because those lymphocytes , and no others , have a protein lock ( known as CD4 ) that can be picked by yet another viral protein - - gp120. But a few non - lymphocytes also sport CD4. Macrophages - - which assist the immune system by eating bacteria - - sometimes carry it . So do some brain cells . And macrophages and T - cells can make their way into the brain . This is a place where many drugs cannot follow them , due to a phenomenon known as the blood - brain barrier that serves to cushion the body 's most vital organ from rude physiological shocks .

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The brain , therefore , may serve as a reservoir of last resort for the virus. ( Indeed , several researchers believe that the dementia suffered by some AIDS patients is nothing to do with the collapse of their immune systems , but is a direct effect of the virus on nerve cells ) . So the test of how well the protease - blocker - based triple - drug therapies can really do will come when some of those who appear to be free of the virus are taken off the drugs . Dr Ho and Dr Markowitz plan to offer this possibility to their patients when they have been on the treatment for a year ( that is , within the next couple of months for the earliest recruits ) , provided that a detailed scrutiny of their lymph nodes shows those to be as virus - free as their blood is .

Dr Ho and Dr Markowitz are optimistic . But their current subjects are people who were infected with the virus only recently , and their optimism extends only as far as those who start treatment within three months of acquiring their unwelcome viral passengers . Even that , though , would be a powerful sign . To suggest that HIV in any shape or form could be cleared from anyone would be a great leap forward . It is not a cure , not quite yet . But , for the first time since 1981, when a few inquisitive doctors noticed the outbreak of a strange and rare cancer in gay American men , there is hope .

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