The donor turned out to be a gay man who had contracted the virus during the late 1970s or early ’80s, then given blood at least 26 times before learning he was infected. After tracking him down, Tindall learned, to his amazement, that the man was just as healthy as the people who got his blood. “We know that HIV causes AIDS,” Tindall says. “We also know that a few patients remain well for long periods, but we’ve never known why. Is it the vitamins they take? Is it some gene they have in common? This work suggests it has more to do with the virus. I think we’ve found a harmless strain.”
He may also have found the viral equivalent of a fossil, a clue to the origin, evolution and future of the AIDS epidemic. HIV may not be a new and inherently deadly virus, as is commonly assumed, but an old one that has recently acquired deadly tendencies. In a forthcoming book, Paul Ewald, an evolutionary biologist at Amherst College, argues that HIV may have infected people benignly for decades, even centuries, before it started causing AIDS. He traces its virulence to the social upheavals of the 1960s and ’70s, which not only sped its movement through populations but rewarded it for reproducing more aggressively within the body.
The idea may sound radical, but it’s not just flashy speculation. It reflects a growing awareness that parasites, like everything else in nature, evolve by natural selection, changing their character to adapt to their environments. Besides transforming our understanding of AIDS, the new view could yield bold strategies for fighting it. Viruses can evolve tens of thousands of times faster than plants or animals, and few evolve as fast as HIV. Confronted by a drug or an immune reaction, the virus readily mutates out of its range. A few researchers are now trying to exploit that very talent, using drugs to force HIV to mutate until it can no longer function. A Boston team, led by medical student Yung-Kang Chow, made headlines last month by showing that the technique works perfectly in a test tube. Human trials are now in the works, but better drug treatment isn’t the only hope rising from an evolutionary outlook. If rapid spread is what turned HIV into a killer, then condoms and clean needles may ultimately do more than prevent new infections. Used widely enough, they might drive the AIDS virus toward the benign form sighted in Australia.
Viruses are the ultimate parasites. Unlike bacteria, which absorb nutrients, excrete waste and reproduce by dividing, they have no life of their own. They’re mere shreds of genetic information, encoded in DNA or RNA, that can integrate themselves into a living cell and use its machinery to run off copies of themselves. Where the first one came from is anyone’s guess, but today’s viruses are, like any plant or animal, simply descendants of earlier forms.
Most scientists agree that the human immunodeficiency viruses–HIV-1 and HIV-2–are basically ape or monkey viruses. Both HIVs are genetically similar to viruses found in African primates, the so-called SIVs. In fact, as the accompanying tree illustrates, the HIVs have more in common with simian viruses than they do with each other. HIV-2, found mainly in West Africa, is so similar to the SIV that infects the sooty mangabey-an ash-colored monkey from the same region-that it doesn’t really qualify as a separate viral species. “When you see HIV-2,” says Gerald Myers, head of the HIV database project at the Los Alamos National Laboratory, “you may not be looking at a human virus but at a mangabey virus in a human.” HIV-1, the virus responsible for the vast majority of the world’s AIDS cases, bears no great resemblance to HIV-2 or the monkey SIVs, but it’s very similar to SIVcpz, a virus recovered in 1990 from a wild chimpanzee in the West African nation of Gabon.
The prevailing theory holds that humans were first infected through direct contact with primates, and that the SIVs they contracted have since diverged by varying degrees from their ancestors. It’s possible, of course, that the HIVs and SIVs evolved separately, or even that humans were the original carriers. But the primates-to-people scenario has a couple of points in its favor. First, the SIVs are more varied than the HIVS, which suggests they’ve been evolving longer. Second, it’s easier to imagine people being infected by chimps or monkeys than vice versa. Humans have hunted and handled other primates for thousands of years. Anyone who was bitten or scratched, or who cut himself butchering an animal, could have gotten infected.
Until recently, it was unclear whether people could contract SIV directly from primates, but a couple of recent accidents have settled that issue. In one case, reported last summer by the Centers for Disease Control, a lab technician at a primate-research center jabbed herself with a needle containing blood from an infected macaque. The infection didn’t take-she produced antibodies to SIV only for a few months-but she was just lucky. Another lab worker, who handled monkey tissues while suffering from skin lesions, has remained SIV-positive for two years. In a recent survey of 472 blood samples drawn from primate handlers, health officials found that three of those tested positive as well. No one knows whether the people with SIV eventually develop AIDS, but the potential for cross-species transmission is now clear.
Far less clear is when the first such transmission took place. The most common view holds that since AIDS is a new epidemic, the responsible viruses must have entered humans within the past few decades. That’s a reasonable suspicion, but it raises a sticky question. Why, if people have been handling primates in Africa for thousands of years, did SIV take until now to jump species?
One possibility is that humans recently opened some avenue that hasn’t existed in the past. Some theorists argue, for example, that AIDS was spawned by a polio-vaccination program carried out in Africa during the late 1950s. During that four-year effort, 325,000 Africans received an oral polio vaccine produced in kidney cells from African green monkeys. Even if the vaccine was contaminated with SIV-which hasn’t been established-blaming it for AIDS would be hasty. For the SIVS found in African green monkeys bear too little resemblance to HIV-1, the primary human AIDS virus, to be its likely progenitor. In order to link HIV-1 to those early lots of polio vaccine, someone would have to show that they contained a monkey virus never yet found in actual monkeys.
The alternative view-that the HIVs are old viruses-is just as hard to prove, but it requires fewer tortured assumptions. Dr. Jay Levy, an AIDS researcher at the University of California, San Francisco, puts it this way: “We know that all these other primates harbor lentiviruses [the class that includes the SIVs and HIVS]. Why should humans be any exception?” If the HIVs were on hand before the AIDS epidemic began, the key question is not where they came from but whether they always caused the disease.
If HIV had always caused AIDS, one would expect virus and illness to emerge together in the historical record. Antibodies to HIV have been detected in rare blood samples dating back to 1959, yet the first African AIDS cases were described in the early 1980s, when the disease started decimating the cities of Rwanda, Zaire, Zambia and Uganda. When Dr. Robert Biggar, an epidemiologist at the National Cancer Institute, pored over African hospital records looking for earlier descriptions of AIDS-like illness, he didn’t find any. It’s possible, of course, that the disease was there all along, just too rare to be recognized as a distinct condition. But the alternative view is worth considering. There are intriguing hints that HIV hasn’t always been so deadly.
Any population of living things, from fungi to rhinoceri, includes genetically varied individuals, which pass essential traits along to their progeny. As Charles Darwin discerned more than a century ago, the individuals best designed to exploit a particular environment tend to produce the greatest number of viable offspring. As generations pass, beneficial traits become more and more pervasive in the population. There’s no universal recipe for reproductive success; different environments favor different traits. But by preserving some and discarding others, every environment molds the species it supports.
Viruses aren’t exempt from the process. Their purpose, from a Darwinian perspective, is simply to make as many copies of themselves as they can. Other things being equal, those that replicate fastest will become the most plentiful within the host, and so stand the best chance of infecting other hosts on contact. But there’s a catch. If a microbe reproduces too aggressively inside its host, or invades too many different tissues, it may kill the host-and itself-without getting passed along at all. The most successful virus, then, is not necessarily the most or the least virulent. It’s one that exploits its host most effectively.
As Ewald and others have shown, that mandate can drive different microbes to very different levels of nastiness. Because they travel via social contact between people, cold and flu viruses can’t normally afford to immobilize us. To stay in business, they need hosts who are out coughing, sneezing, shaking hands and sharing pencils. But the incentives change when a parasite has other ways of getting around. Consider tuberculosis or diphtheria. Both deadly diseases are caused by bacteria that can survive for weeks or months outside the body. They can reproduce aggressively in the host, ride a cough into the external environment then wait patiently for another host to come along. By the same token, a parasite that can travel from person to person via mosquito or some other vector has little reason to be gentle. As long as malaria sufferers can still feed hungry mosquitoes, their misery is of little consequence to the microbe. Indeed, a host who can’t wield a fly swatter may be preferable to one who can.
These patterns aren’t set in stone. A shift in circumstances may push a normally mild-mannered parasite toward virulence, or vice versa. One of the most devastating plagues in human history was caused by a mere influenza virus, which swept the globe in 1918, leaving 20 million corpses in its wake. Many experts still regard the disaster as an accident, triggered by the random reshuffling of viral genes. But from an evolutionary perspective, it’s no coincidence that the flu grew so deadly when it did. World War I was raging in 1918. Great numbers of soldiers were huddled in the European trenches, where even the most ravaged host stood an excellent chance of infecting many others. For a flu virus, the incentives favoring restraint would have vanished in those circumstances. Rather than rendering the host useless, extreme virulence would simply make him more infectious.
Ewald suspects that HIV has recently undergone a similar transformation. Unlike influenza viruses, which infect cells in the respiratory tract and spread through coughs and sneezes, the HIVs insinuate themselves into white blood cells. Infected cells (or the new viruses they produce) can pass between people, but only during sex or other exchanges of body fluid. Confined to an isolated population where no carrier had numerous sex partners, a virus like HIV would gain nothing from replicating aggressively within the body; it would do best to lie low, leaving the host alive and mildly infectious for many years. But if people’s sexual networks suddenly expanded, fresh hosts would become more plentiful, and infected hosts more dispensable. An HIV strain that replicated wildly might kill people in three years instead of 30, but by making them more infectious while they lasted, it would still come out ahead.
Is that what actually happened? There’s no question that social changes have hastened the spread of HIV. Starting in the 1960s, war, tourism and commercial trucking forced the outside world on Africa’s once isolated villages. At the same time, drought and industrialization prompted mass migrations from the countryside into newly teeming cities. Western monogamy had never been common in Africa, but as the French medical historian Mirko Grmek notes in his book “History of AIDS,” urbanization shattered social structures that had long constrained sexual behavior. Prostitution exploded, and venereal disease flourished. Hypodermic needles came into wide use during the same period, creating yet another mode of infection. Did these trends actually turn a chronic but relatively benign infection into a killer? The evidence is circumstantial, but it’s hard to discount.
If Ewald is right, and HIV’s deadliness is a consequence of its rapid spread, then the nastiest strains should show up in the populations where it’s moving the fastest. To a surprising degree, they do. It’s well known, for example, that HIV-2 is far less virulent than HIV-1. “Going on what we’ve seen so far, we’d have to say that HIV-1 causes AIDS in 90 percent of those infected, while HIV-2 causes AIDS in 10 percent or less,” says Harvard AIDS specialist Max Essex. “Maybe everyone infected with HIV-2 will progress to AIDS after 40 or 50 years, but that’s still in the realm of reduced virulence.” From Ewald’s perspective, it’s no surprise that HIV-2, the strain found in West Africa, is the gentle one. West Africa has escaped much of the war, drought and urbanization that fueled the spread of HIV-1 in the central and eastern parts of the continent. “HIV-2 appears to be adapted for slow transmission in areas with lower sexual contact,” he concludes, “and HIV-1 for more rapid transmission in areas with higher sexual contact.”
The same pattern shows up in the way each virus affects different populations. HIV-2 appears particularly mild in the stable and isolated West African nation of Senegal. After following a group of Senegalese prostitutes for six years, Harvard researchers found that those testing positive for HIV-2 showed virtually no sign of illness. In laboratory tests, researchers at the University of Alabama found that Senegalese HIV-2 didn’t even kill white blood cells when allowed to infect them in a test tube. Yet HIV-2 is a killer in the more urban and less tradition-bound Ivory Coast. In a survey of hospital patients in the city of Abidjan, researchers from the U.S. Centers for Disease Control found that HIV-2 was associated with AIDS nearly as often as HIV-1.
The variations within HIV-1 are less clear-cut, but they, too, lend support to Ewald’s idea. Though the evidence is mixed, there are hints that IV drug users (whose transmission rates have remained high for the past decade) may be contracting deadlier strains of HIV-1 than gay men (whose transmission rates have plummeted). In a 1990 study of infected gay men, fewer than 8 percent of those not receiving early treatment developed AIDS each year. In a more recent study of IV drug users, the proportion of untreated carriers developing AIDS each year was more than 17 percent.
Together, these disparities suggest that HIV assumes different personalities in different settings, becoming more aggressive when it’s traveling rapidly through a population. But because so many factors affect the health of infected people, the strength of the connection is unclear. “This is exactly the right way to think about virulence,” says virologist Stephen Morse of New York’s Rockefeller University. “Virulence should be dynamic, not static. The question is, how dynamic? We know that a pathogen like HIV has a wide range of potentials, but we can’t yet say just what pressures are needed to generate a particular outcome.”
The best answers to Morse’s question may come from laboratory studies. A handful of biologists are now devising test-tube experiments to see more precisely how transmission rates shape a parasite’s character. Zoologist James Bull of the University of Texas at Austin has shown, for example, that a bacteriophage (a virus that infects bacteria) kills bacterial cells with great abandon when placed in a test tube and given plenty of new cells to infect. Like HIV in a large, active sexual network, it can afford to kill individual hosts without wiping itself out in the process. Yet the same virus becomes benign when confined to individual cells and their offspring (a situation perhaps akin to pre-epidemic HIV’s). With a good animal model, researchers might someday manage to test Ewald’s hypotheses about HIV with the same kind of precision.
Until recently, medical science seemed well on its way to controlling the microbial world. Yet after 10 years and billions of dollars in research, HIV still has scientists over a barrel. The secret of its success can be summed up in one word: mutability. Because HIV’s method of replication is so error prone (its genes mutate at a million times the rate of our own), it produces extremely varied offspring, even within an individual host. Whenever a drug or immune response successfully attacks one variant, another arises to flourish in its place. Even when an AIDS drug works broadly enough to check HIV’s growth, it rarely works for long. AZT, for example, can help prevent symptoms for a couple of years. But people on AZT still get AIDS, as the viral populations in their bodies evolve toward resistant forms.
There may,not be a drug or vaccine on earth that could subdue such a protean parasite. But from a Darwinian perspective, killing HIV is not the only way to combat AIDS. We know the virus changes rapidly in response to outside pressures. Logic suggests that if we simply applied the right pressures-within a community, or even within a patient’s body-we might begin to tame it.
It’s well known that condoms and clean needles can save lives by preventing HIV infection. From an evolutionary perspective, there is every reason to think they could do more. Used widely enough, those same humble implements might push the virus toward more benevolent forms, simply by depriving virulent strains of the high transmission rates they need to survive. Gay men are already engaged in that exercise. Studies suggest that, thanks to safer sex, the rate of new infections among gays declined five- to tenfold during the 1980s. There are tantalizing hints that HIV has grown less noxious in the same population over the same period. In a 1991 study, researchers at the National Institutes of Health (NIH) calculated the rates at which infected people from different risk groups were developing AIDS each year. They found that as of 1987, the rate declined sharply among gay men, suggesting the virus was taking longer to cause illness. Part of the change was due to AZT, which can delay the onset of symptoms. But when the NIH researchers corrected for AZT use, there was still a mysterious shortage of AIDS cases. From Ewald’s viewpoint, the shortfall was not only unsurprising but predictable.
How far could such a trend be pushed? Would broader, better prevention efforts eventually turn today’s deadliest HIV-1 into something as benign as Senegal’s HIV-2? No one knows. But the prospect of domesticating the AIDS virus, even partially, should excite public-health officials. Condoms and clean needles are exceedingly cheap medicine. They can save lives even if they fail to change the course of evolution-and judging from the available evidence, they might well succeed.
In the meantime, more than 12 million people are carrying today’s HIV, and those who get AIDS are still dying. Fortunately, as Yung-Kang Chow and his colleagues at Massachusetts General Hospital showed last month, there’s more than one way to manipulate viral evolution. The researchers managed, in a test-tube experiment, to outsmart HIV at its own game. Their trick was to combine three drugs-AZT, ddI and pyridinone-that disarm the same part of the virus (an enzyme called reverse transcriptase).
Any of those drugs can foil HIV’s efforts to colonize host cells. When HIV encounters them individually, or even in pairs, it gradually mutates into resistant forms and goes on about its business. But each mutation makes the virus slightly less efficient-and as Chow’s group demonstrated, there comes a point where mutation itself hobbles the virus (chart). By engineering an HIV mutant that contained three different mutations (one in response to each of the three drugs), the researchers ended up with a virus that was too deformed to function at all. If virgin HIV can’t function in the presence of the three drugs-and if triply mutated HIV can’t function at all-then the three-drug regimen should, theoretically, do wonders for patients.
It’s a long way from the test tube to the clinic; many treatments have shown great promise in lab experiments, only to prove ineffective or highly toxic in people. Upcoming clinical trials will determine whether patients actually benefit from Chow’s combination of drugs. The beauty of the new approach, however, is that it’s not limited to any particular combination. While the Boston team experiments with drugs directed against reverse transcriptase, researchers at New York’s Aaron Diamond AIDS Research Center are trying the same tack against another viral target (an enzyme called protease). “This virus has impressed us again and again with its ability to change,” says Dr. David Ho, director of the Aaron Diamond Center. “It always has a new strategy to counter our efforts. Now we’re asking it to make a trade-off. We’re saying, ‘Go ahead and mutate, because we think that if you mutate in the right place, you’ll do less damage to the patient’.”
The forces that brought us this plague can surely bring us others. By encroaching on rain forests and wilderness areas, humanity is placing itself in ever-closer contact with other animal species and their obscure, deadly parasites. Other activities, from irrigation to the construction of dams and cities, can create new diseases by expanding the range of the rodents or insects that carry them. Stephen Morse, the Rockefeller virologist, studies the movement of microbes among populations and species, and he worries that human activities are speeding the flow of viral traffic. More than a dozen new diseases have shown up in humans since the 1960s, nearly all of them the result of once exotic parasites exploiting new opportunities. “The primary problem,” Morse concludes, “is no longer virological but social.”
The Ebola virus is often cited as an example of the spooky pathogens in our future. The virus first struck in August 1976, when a trader arrived at a mission hospital in northern Zaire, fever raging and blood oozing from every orifice. Within days the man died, and nearly half of the nurses at the hospital were stricken. Thirty-nine died, and as hospital patients contracted the virus, it spread to 58 neighboring villages. Ebola fever ended up striking 1,000 people in Zaire and nearby Sudan, killing 500. Epidemiologists feared it would spread more widely, but the outbreaks subsided as quickly as they had beg-un. From a Darwinian perspective, that’s no great surprise. A parasite that kills that rapidly has little chance of sustaining a chain of infection unless it can survive independently of its host.
More worrisome is a virus like HTLV, a relative of HIV that infects the same class of blood cells and is riding the same waves through new populations. Though recognized only since the 1970s, the HTLVs (HTLV-1 and HTLV-2) appear to be ancient. About one in 20 HTLV-1 infections leads eventually to leukemia, lymphoma or a paralyzing neurologic disorder called TSP. The virus is less aggressive than HIV-1-it typically takes several decades to cause any illness-but its virulence seems to vary markedly from one setting to the next. In Japan, the HTLV-related cancers typically show up in 60-year-olds who were infected by their mothers in the womb. In the Caribbean, where the virus is more often transmitted through sex, the average latency is much shorter. It’s not unusual for people to develop symptoms in their 40s.
HTLV may not mutate as readily as HIV, but it is subject to the same natural forces. If human activities can turn one virus into a global killer, it’s only prudent to suspect they could do the same to another. “HTLV is a threat,” says Ewald, “not because it has escaped from some secluded source, but because it may evolve increased virulence.” HTLV-1 is only one tenth as prevalent as HIV in the United States, but it has gained a strong foothold among IV drug users, whose shared needles are a perfect breeding ground for virulent strains.
No one knows whether HTLV could cause an epidemic like AIDS. Fortunately, we don’t have to wait passively to find out. We’re beginning to see how our actions mold the character of our parasites. No one saw the last epidemic coming. This time, that’s not an excuse.
Worldwide, more than 12 million people are infected with HIV. The great majority live in Africa, south of the Sahara. But as the inset shows, Asia is poised to become the plague’s next epicenter.
COUNTRY HIV Infections North America 1 million+ Latin America/Caribbean 1 million+ Western Europe 500,000 North Africa/Middle East 750,000+ Sub-Saharan Africa 7.5 million+ Eastern Europe/Central Asia 50,000 East Asia 25,000 Southeast Asia 1.5 million Australia 25,000+ HARNESSING EVOLUTION IN THE LAB Because HIV mutates so rapidly, no single drug subdues it for long. But in test-tube studies, researchers at Massachusetts General Hospital used a combination of three drugs to force it to mutate until it could no longer function. 1 In response to AZT, the first drug, HIV’s genetic sequence changes. Even so, the virus remains viable and able to replicate. 2 Resistance to a second drug, ddI, requires another mutation, but still the virus is able to reproduce itself. 3 The third drug, pyridinone, provokes a final mutation, which, in combination with the previous changes, robs the virus of its ability to replicate. DIAGRAM: HIV mutations (ROHR–NEWSWEEK)
AS HUMAN HABITS CHANGE, NEW VIRUSES EMERGE VIRUS, DISEASE JUNIN Argentine Hemorrhagic Fever SYMPTOMS Fever, muscle pain, rash, internal bleeding and, sometimes, tremors or convulsions. Mortality rate: 10 to 20 percent. ORIGIN First recognized in 1953, Junin has emerged as a result of an increase in corn cultivation in northern Argentina. Carried by mice. STATUS A rodent-control program brought the virus’s Bolivian cousin, Machupo, under control, but Junin has expanded its reach in recent decades. It strikes 400 to 600 people annually.
VIRUS, DISEASE EBOLA African Hemorrhagic Fever SYMPTOMS Fever, vomiting, rash, muscle pain, gastrointestinal bleeding, shock. A deadly virus, Ebola kills at least half its victims. ORIGIN Virtually identical to Marburg, a virus found in Germany in 1967, Ebola was first reported in 1976. Its origin is unknown. STATUS An outbreak in Africa killed 500 in 1976. Philippine monkeys sent to Reston, Va., research lab brought a related-but not lethal-virus here in 1989, leading to curbs on monkey imports.
VIRUS, DISEASE DENGUE Dengue Fever SYMPTOMS Headache, fever, muscle pain, chills. More severe dengue hemorrhagic fever can cause internal bleeding and death. ORIGIN Dengue has long plagued tropical Asia, South America and the Caribbean, favoring densely populated, mosquito-infested areas. STATUS Infects more than 30 million people annually. Rare in U.S. but could spread more widely since a shipment of used tires brought virus-transmitting Asian tiger mosquitos ashore in 1985.
VIRUS, DISEASE HTLVs Leukemia, TSP SYMPTOMS Leukemia is a cancer of white blood cells which can spread to other organs. TSP is a degenerative neurological disorder. ORIGIN HTLV-1 was first reported in 1980, but studies suggest that it and the related virus HTLV-2 have attacked humans for millenniums. STATUS HTLVs are transmitted in the same manner as HIV but, so far, appear less deadly. One recent study found that up to 20 percent of IV drug users in Los Angeles are infected. SOURCE: STEPHEN S. MORSE–THE ROCKEFELLER UNIVERSITY, PAUL EWALD–AMHERST COLLEGE
A HYPOTHETICAL HISTORY OF AIDS Why did HIV suddenly emerge as a global killer? According to one theory, the virus has infected people for centuries, but recent social changes have altered its character.
BEFORE 1960
Rural Africans contracted benign ancestral forms of HIV from primates. Because the viruses spread so slowly among people, they couldn’t afford to become virulent.
1960 TO 1975
War, drought, commerce and urbanization shattered African social institutions. HIV spread so rapidly, becoming more virulent as transmission accelerated.
1975 TO PRESENT
Global travel placed HIV in broader circulation. Shifting sexual mores and modern medical practices, such as blood transfusion, made many populations susceptible.
THE FUTURE
If social changes can turn a benign virus deadly, the process should be reversible. Simply slowing transmission may help drive fast-killing strains out of circulation.
