After a decade of disappointments, AIDS researchers may finally have blown the virus’s cover. A flurry of recent studies using new and more powerful antiviral drugs have captured a radically new picture of how the virus overwhelms the immune system. While it may take years for a person infected with the virus to get sick and die, that does not mean the virus is slow moving; all the while, it now seems, a silent but feverish battle is under way in the patient’s blood, with more than a billion immune cells being sacrificed each day to hold the line against a rapidly proliferating virus--which ultimately triumphs by the sheer force of its even greater numbers. This frightening-sounding picture, AIDS researchers are saying, just might--might--be good news. If the infection is caught early enough, before the tide has turned irrevocably against the immune-system defenders, combinations of antiviral drugs might hold the virus in check. We might then be able to live with it.
Until now, one of the central puzzles of AIDS has been the presence in the blood of such low levels of HIV, the human immunodeficiency virus. Shortly after a person becomes infected, the virus count in the blood rises, prompting an aggressive immune response. The blood level of the virus then drops, and it apparently retreats to the lymph nodes and other hiding places. It may take years for the virus count to rise again-- but eventually it almost always does. At that point the virus begins to wipe out T4 cells, and the disease enters its debilitating stage. T4 cells are the beat cops of the immune system, the ones that call in reinforcements whenever they encounter a cell infected by any kind of virus; as their numbers slowly dwindle, the patient falls prey to the opportunistic infections that ultimately, almost invariably, kill him.
Yet even in late-stage patients, the amount of virus in the blood and the number of infected T4 cells have often seemed too small to cause the immune collapse that is the hallmark of AIDS. Complicated hypotheses have been adduced to explain this paradox. Maybe the virus doesn’t do its damage directly, some researchers have suggested; maybe it somehow alters the immune system’s ability to regulate itself, so that perfectly healthy immune cells start committing suicide or start attacking other perfectly healthy immune cells. Those hypotheses only raised another question: If the virus replicates too slowly to cause so much damage on its own, why do patients with late-stage AIDS harbor so many mutant strains of it-- mutations that would seem to require countless generations of viruses to produce?
The answer, it appears, is that the virus isn’t replicating slowly at all. It is replicating extremely fast--but so are the T4 cells that are struggling desperately to clear it and the cells it has infected from the blood. In fact, the two are reproducing at almost the same rate, which is apparently why the progress of the disease is so gradual. It’s the virus constantly chewing on the immune system that eventually leads to AIDS, says microbiologist John Coffin of Tufts University. And this progression is largely occurring during a period when not much seems to be happening.
Virologist David Ho of the Aaron Diamond AIDS Research Center in New York City and his colleagues were able to see what was really happening thanks to a new antiviral drug they’re testing in clinical trials. The drug, called ABT-538, is designed to block the action of an enzyme called a protease that the virus needs to finish making copies of itself. (AZT, a common anti-AIDS drug, blocks a different enzyme, reverse transcriptase, which the virus uses at an earlier stage of its life cycle to transcribe its RNA into a cell’s DNA.) Ho’s team administered ABT-538 to 20 patients, most of whom had advanced AIDS.
The drug worked remarkably well, at least initially. Before treatment, the patients’ virus count and their number of T4 cells varied little from day to day. After treatment, however, the amount of virus in the blood dropped to less than 1 percent of the pretreatment level. It didn’t vanish entirely, either because the drug didn’t spread through all infected tissues or because mutants that could resist the drug already existed. But in every case, the patients’ T4 cell counts rebounded. One man’s count rose from 68 to 680 cells per cubic millimeter, an amount that approaches the norm of 800 to 1,000.
Besides suggesting that ABT-538 has promise as an AIDS drug, this result revealed the heated race that goes on between virus and immune cell. It’s similar to a person running on a treadmill, says Ho. If you can’t see his feet, you don’t know how fast the treadmill’s moving or how hard he’s working. But all of a sudden, if you apply the brakes, then the speed with which this guy moves forward tells you what’s been going on.
By measuring how quickly T4 cells reappeared once the brakes were applied--in the form of ABT-538--Ho and his colleagues calculated that before treatment their patients had been pumping out well over a billion T4 cells each day. That’s an incredibly accelerated rate--between 25 and 75 times the rate seen in patients with less-advanced infections. But it still wasn’t enough to keep them ahead of the rapidly replicating virus, which was infecting and killing each new cell in less than two days. The patients were running as fast as they could--and they were still losing ground on the treadmill.
Such rapid viral replication countered by a strong immune response is not unknown; on the contrary, it’s characteristic of acute, short-lived viral infections, such as measles or the flu. But in those infections, the immune system usually wins: it rids the body of the virus and builds resistance to future infection. Why can’t it triumph over HIV? Ho suspects that the very length and intensity of the struggle ultimately do in the immune system by encouraging the emergence of mutant viruses that can outstrip its defenses. A similar idea was proposed a few years ago, on the basis of a computer model, by mathematical biologists Robert May and Martin Nowak of Oxford University.
When patients are first infected, Ho explains, they receive a relatively uniform HIV population. Although many strains of the virus must exist in the person transmitting it, only those strains that can successfully infect macrophages--immune sentries that patrol tissue and eat up foreign invaders--gain a foothold in the recipient. In macrophages, HIV seems to replicate slowly, and it doesn’t do much visible harm to infected cells. But the same cell-surface receptors that allow HIV to gain entry to a macrophage, hijack its DNA, and begin copying itself also exist on other immune cells. They’re especially abundant on T4 cells, and soon the virus makes the jump to them. For reasons that are still not clear, the virus then starts to reproduce much faster--every day, it now seems. A virus in a patient who has been infected for ten years, then, may be 3,000 generations removed from the original infecting virus.
That creates a lot of opportunity for evolution, because genetic mutations occur most commonly during replication. Some mutations will weaken the virus in such a way as to expose it to attack by the vigilant immune system. But other mutations will aid the virus, speeding its replication and increasing the chances it can evade the immune defenders. Because the virus gets so many chances to replicate, says Ho, it evolves and mutates, and those strains with the greatest replication efficiency will gradually win out. This is a Darwinian evolution going on in one patient.
By the late stages of the disease, the patient may have as many as a billion strains of HIV in his body. With so many variants around, sooner or later some are bound to emerge that are resistant to any given drug. Indeed, resistant strains cropped up in some of Ho’s patients within weeks after they were treated with ABT-538, and their viral levels began to climb again. How do we deal with this? asks Ho. By not letting rounds and rounds of replication go on. It’s the same as letting a cancer go years and years before you treat it. Until now, though, we haven’t had good tools.
Treating HIV-positive people before they show symptoms is not the norm right now, but Ho thinks ABT-538 might be much more effective if it is given as soon after infection as possible, while patients harbor many fewer strains of the virus. Even so, a single drug is not likely to be the solution to AIDS, especially for the majority of patients, who only learn of their infection long after it has happened. Most researchers think a drug combination is the way to go. One logical strategy would be to combine drugs that attack the virus in different parts of its life cycle. But researchers at Wellcome Research Laboratories in England have reported promising results with a combination of AZT and a drug called 3TC, both of which attack reverse transcriptase; mutant viruses that resisted 3TC were apparently vulnerable to AZT.
A more solid basis for (cautious) optimism than any one clinical trial, however, is the change in perspective created by Ho’s study and by similar results reported at the same time by George Shaw of the University of Alabama and his colleagues. If people succumb to AIDS simply because their immune systems are overwhelmed--if the battle against AIDS is a numbers battle--then the goal also becomes simple and perhaps more attainable: keep the virus count down and the T4 count up. A drug may help achieve that goal even if resistant mutants crop up, says Ho, because those mutants are liable to replicate more slowly. If the virus mutates, it usually pays a price, however small, he says. If you make the virus pay each time you throw a drug at it, it’s sacrificing something, hopefully its ability to replicate--or to kill.
The few long-term survivors of HIV infection prove it can be done: their bodies are apparently keeping up with the viral treadmill even without the help of drugs. According to work by Ho’s team and others, HIV- infected patients who have remained symptom-free for more than a decade tend to carry a very low level of the virus--about 1 percent of what is found in patients whose disease is progressing. The experience of the survivors provides a clue to how much HIV the body can bear before showing symptoms. In these patients we have concrete numbers to work with, says Ho. They serve as a guidepost for our therapies. If we could bring the virus to levels we find in long-term survivors, maybe the patients could deal with this on their own.
