http://www.nytimes.com/2001/09/04/health/anatomy/04ORIG.html

September 4, 2001

AIDS AT 20 / WHERE IT ALL STARTED

The Genesis of an Epidemic: Humans, Chimps and a Virus

By GINA KOLATA

hree years ago, Dr. Beatrice Hahn got a call from a colleague asking if she wanted some body parts from a chimpanzee that had died a decade ago.

The colleague said, "I have the spleen, the brain and the lymph nodes in my freezer. I need to clean my freezer, so before I throw it out, do you want to look at it?"

Then the scientist said the animal had antibodies in its blood very much like ones that people develop when they are infected with the AIDS virus.

Dr. Hahn leapt at the chance. It was a long shot, but it was possible that the long-dead chimpanzee could be a missing link in the search for the origins of AIDS. A few days later, Federal Express delivered a huge box of frozen chimpanzee parts, packed in dry ice, to Dr. Hahn's laboratory at the University of Alabama at Birmingham, where she is a professor of medicine.

Three days later, she had her answer. That chimpanzee, which had been healthy until she died in childbirth at age 26, held clues that eventually enabled Dr. Hahn and an international group of 11 others to unravel the mystery of the origin of the epidemic. It was a mystery that took years to solve and that had frustrated researchers and the public, stunned by the sudden emergence of such a terrible new disease.

Some said AIDS was caused by a mutant virus, a sort of Andromeda strain. Others favored conspiracy theories suggesting that H.I.V. had been created by scientists and escaped from germ warfare labs. There was a Western medicine disaster theory, which held that the virus was injected into Africans in bad batches of polio vaccine.

Then there was a more pedestrian idea — that people got H.I.V. from primates in Africa.

Scientists tended to favor the primate hypothesis because they knew that diseases can jump from animals to people. Dengue fever, Hanta virus, influenza and hepatitis B all originated in other species. But, researchers learned, it was not easy to trace the virus causing the human AIDS epidemic, H.I.V.-1, to an animal. And even when they started seeing provocative hints about the origins of AIDS, those hints soon turned contradictory.

The first evidence that H.I.V.-1 jumped to humans from primates came about a decade ago, when scientists isolated a virus from an African chimpanzee that very closely resembled the AIDS virus now infecting tens of millions of people. The chimpanzee virus looked so much like H.I.V.-1 that it was almost irresistible to think that the animals had somehow given the virus to people. Its genes were arranged the same way, and it even had a distinctive gene, called vpu, that had never been seen in any other virus.

While AIDS-like viruses were starting to emerge in other primates and in other animals, none looked so much like H.I.V.-1 as this chimpanzee one did.

Adding to the evidence was a tantalizing snippet of another AIDS-like virus found in a tube of blood from a baby chimpanzee that had died. While the fragment was too small for anyone to be certain that it closely resembled H.I.V.-1, the genetic sequence from this second chimp lined up exactly with a piece of the first chimpanzee's virus.

But soon the picture became clouded. A few years ago, scientists found a third chimpanzee with an AIDS-like virus, but when they analyzed that virus, they discovered that it was only distantly related to H.I.V.- 1. So, some asked, were chimpanzees really the source of the human AIDS epidemic? Or were chimpanzees, and humans, becoming infected by some other animals?

One way to find out would be to study wild chimpanzees and see whether they had a virus like the human form, H.I.V.-1, whether they had a different virus like the third chimpanzee's virus or whether they were infected with a variety of AIDS- like viruses. But the only way to find viruses was to look for them in blood. And researchers could not draw blood from the elusive animals without stunning them first with a tranquilizer gun, and the stunning effort was impractical.

To make matters worse, no one could show that the animal with a virus like H.I.V.-1 came from the region where the human epidemic first exploded.

That was when Dr. Hahn examined the frozen chimpanzee organs, and the mystery began to crack. That animal, she discovered, also had a virus in its tissues that looked like H.I.V.-1.

Suddenly, said Dr. Edward Holmes, an evolutionary biologist at Oxford University, he and others who had questioned whether chimpanzees really were the source of H.I.V.-1 in humans, became convinced. While scientists had found only two, or possibly three chimpanzees that had the virus, Dr. Hahn's information, added to three other lines of evidence, was enough.

One line of evidence pointed to west-central Africa — a region where chimpanzees live — as the place where the human AIDS epidemic began.

Scientists, analyzing the genetic sequences of AIDS viruses found in patients from around the world, were discovering that the viruses in west- central Africa were the most diverse. And it is a general rule that the more diverse an organism's genes are, the longer it has been around. That is because as the years go by more and more variations accumulate in an organism's genes.

For example, Dr. Holmes said, human DNA is most diverse in Africa, supporting the idea that the human species originated on that continent.

The second line of evidence was a plausible way for the virus to get from chimpanzees to humans. People in west-central Africa eat chimpanzees. It was entirely reasonable to think that an infected animal's blood gave the virus to a person who was handling the chimpanzee meat, infecting the person and setting the stage for an AIDS epidemic.

"People eat chimpanzees," Dr. Hahn said. "We expect that transmissions occurred through the exposure to blood through hunting or preparation of meat."

Finally, researchers were discovering AIDS-like viruses in other animals and other primates in Africa, but none were as closely related to H.I.V.-1 as the viruses in the three chimpanzees.

The only species that fit all the evidence as the source of H.I.V.-1 was the chimpanzee, Dr. Holmes said.

A scientific paper that Dr. Hahn had published about the frozen chimpanzee "was extraordinarily important," Dr. Holmes said. "It really made people believe that chimps were the ancestral species."

Dr. Paul M. Sharp, a professor of genetics at the University of Nottingham who worked on the analyses of the viruses, said: "It had been a gradual shift in our perceptions. At first we had been saying that either chimps are the source or they are recipients, like humans." Dr. Hahn's chimp made all the difference, Dr. Sharp said.

Now, researchers say, they have found two more chimpanzees that were infected in the wild with a virus like H.I.V.-1. The animals were among a group of 29 captured in Cameroon, in the west-central region of Africa.

It would be ideal, of course, to find stored blood from the original people who contracted H.I.V.-1 and stored tissue from chimpanzees in the same area, and then show they had exactly the same virus, Dr. Holmes said. But, he added, that is not going to happen.

"You haven't got a smoking gun, but you're never going to have one," Dr. Holmes said. "The gun's long gone. You're never going to find it."

Yet, he said, there is the virus in chimpanzees, there is the geographical overlap between where chimpanzees live and where H.I.V. started, and there is a mechanism.

"That was it for us," Dr. Holmes said.

But knowing the virus came from chimpanzees left two pressing questions. When did the virus take hold in the human population? And how?

Dr. Bette T. Korber, a molecular geneticist at Los Alamos National Laboratory, and her colleagues had a way to get an answer to the question of when. They had the genetic sequences of viruses isolated from people and knew when those viruses were found, starting with the oldest human H.I.V. sample available. It was from a man in what is now Kinshasa, Congo, in west-central Africa, in 1959.

Since the viruses mutate at a roughly constant rate, the researchers could construct a path of how the virus had mutated and determine how long it would take to move from one virus to another one with the amount of genetic diversity found today. From those calculations, they found a date when the spark of the epidemic was lit: 1931, plus or minus 15 years.

"You might think, if the virus was present in 1930, how on earth did we not see it?" Dr. Korber asked. "But if it is only present in a few thousand individuals and it takes a decade to get sick, it could easily have been missed."

Researchers say the virus almost certainly infected humans repeatedly as they killed and ate chimpanzees over the years, but that it is hard to start an AIDS epidemic. For it to develop, the virus must be prevented from dying with its victims and a steady chain of transmissions must occur.

"We think that these transmissions have gone on forever and a day, for all the centuries that people hunted chimpanzees," Dr. Hahn said. "The rule is that these transmissions go nowhere. They just peter out, unless you have additional factors that promote subsequent spread in the new human host."

One possible explanation for the extensive spread of H.I.V.-1, several scientists said, was that people began congregating in cities in Africa. There, the conditions were ripe for an AIDS epidemic.

"If you look at the population of Kinshasa, it's an exponential curve going up," Dr. Sharp said. "During the 20th century, you have far more movement of people into urban areas and perhaps changes in behavior." In addition, doctors in clinics in Africa commonly reused needles without sterilizing them between patients, a practice that, he said, "would have played a role in getting the virus kick-started."

Another possible explanation is less comforting.

Dr. Korber asked if it was possible that nothing really special made the epidemic grow, other than an initial transmission that, by chance, did not die out. Could a very slow curve of exponential growth, starting around 1930, end up in an epidemic that finally caught the world's attention around 20 years ago?

Her mathematical models showed that it made sense. For the first 30 years, the number of cases would have climbed into the hundreds. As the web of infections grew, the numbers would jump, reaching large numbers in Africa by 1980. At that point, enough people would be infected that the epidemic would be noticed. That model is particularly troubling, Dr. Hahn said.

"If you say, `I don't know how it got started; it could have been this, it could have been that,' and if all you need are a certain set of circumstances in the beginning so that it doesn't die out, then it could happen again," she said.

"People don't want to hear that."

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