This article includes discussion near the end of the article of the future course of HIV after it mutates. Here in the USA and other western countries, HIV mutates after a person develops resistance to a drug. For example, resistance to AZT may cause a person to develop a 215Y mutation, but after transmission to another person through sex or needle sharing it may turn into a 215D; and when the second person develops resistance, the mutation may be 215S. "And that's multidrug resistant HIV," says Dr. Jaap Goudsmit of the University of Amsterdam.

As well, this article suggests the likelihood that various types of monkeys have passed viruses similar to HIV between themselves and to humans over the past recent decades. The particular form of HIV may be harmless to the monkey species that harbors it. Researchers hope they can study this and discover why some monkeys don't get sick while others do. They hope such a discovery might turn into a vaccine or treatment. They say the best place to study this is in the Congo Basin where viruses are passed from one species to another when animals fight amongst themselves and when humans come in contact with blood through butchering the meat for eating.

The Viral Link / Researchers increasingly connect forms of HIV to monkey versions.

Newsday - April 6, 1999
Laurie Garrett - Staff Correspondent
THE ANNOUNCEMENT early this year that the ancestral mother of HIV-1 had been found in a species of West African chimpanzee is now seen as just one of several findings that suggest mankind and monkeys are strongly linked by the viruses they carry, researchers say. In a meeting here of an elite group of about 150 experts on the evolution of viruses, researchers said last week that they had found at least two other forms of the simian version of HIV in the same species of chimpanzee, called Pan troglodytes troglodytes. This mirrors what had previously been seen with the less common HIV-2, which has been irrefutably linked to a similar form of the virus found in sooty mangabey monkeys.

"Contacts between humans and chimpanzees seem to be closer than previously thought," said Jun Takehisa, a researcher at the Institute for Virus Research in Kyoto, Japan. "It may be possible that an identical ancestral virus went from mandrill [monkeys] to chimpanzees, and then to humans."

Speaking before an energized group of scientists at the sixth annual HIV Dynamics and Evolution Conference, Takehisa announced the discovery of a sort of mosaic virus in two Pan troglodytes troglodytes chimps found in Gabon. The virus, he said, appears to be partly made of HIV-1 and partly of some previously unknown form of SIV, or simian AIDS virus.

A French Institut Pasteur team has also found what appears to be an HIV ancestor, in Pan troglodytes troglodytes chimpanzees tested in an animal rescue center in Cameroon. Of 29 chimps tested, three carried a virus that was about 80 percent identical to a type of HIV-1 seen in people.

The first such finding was made by Dr. Beatrice Hahn last year and announced on Feb. 3. Hahn and coworkers at the University of Alabama and other institutes found a virus in two Pan troglodytes troglodytes chimps, dubbed SIVcpzUSA, that is a very close genetic cousin to the oldest known HIV-1 strain.

These three separate findings each yielded different SIVcpz strains but shared key features: All came from Pan troglodytes troglodytes chimps that originated in central west Africa; all are genetically 70 percent to 90 percent identical to human AIDS viruses; and in no case did the viruses appear to sicken the chimps or cause any illness.

So it's probable, experts now say, that HIV-1 did come from chimpanzees and perhaps has been introduced frequently from chimp to human over the last four or five decades. And the same is true in the case of HIV-2, which experts agree originated in sooty mangabey monkeys.

"SIVs have been found now in nine classes of ape and monkey species," said Preston Marx of the Aaron Diamond AIDS Research Center in New York. "We see that all of the HIV-2-related ones are found in sooty mangabeys. And all HIV-2 subtypes occurred only in sooty mangabey ranges where crossover to humans seems to be ongoing.

"And we see that all of the HIV-1-related ones [SIVs] come from chimpanzees," Marx continued, noting that specific types of SIVcpz have been found in three of the four chimp species.

Paul Sharp, of the Institute of Genetics in Nottingham, Britain, thinks that sooty mangabey SIV-2s have probably caused six epidemics in human beings, all of which currently look like a single, West African-focused pandemic. And he says his research suggests that SIV-1 from chimps entered human populations at least three times over the last few decades, beginning in the late 1930s or early 1940s with the SIVcpzUSA strain found by Hahn.

In the monkey and chimp world, the experts say, the SIV picture is clear: Virtually every equatorial African primate species carries a form of SIV that is an ancient virus, passed sexually between the animals and harmless to the species in which it resides.

Sooty mangabeys, for example, have probably carried SIVsm harmlessly in their bodies for more than a million years. But when that sooty mangabey virus gets into another monkey species - rhesus monkeys, for instance - it becomes lethal, sparking epidemics that have probably wiped out clusters of monkeys, unobserved by humans, for centuries.

So why are the SIVs harmless to their primary hosts, but so harmful elsewhere?

That is a question with profound implications, the scientists agreed, holding the key to understanding an effective immune response to these viruses that could, perhaps, be used to develop an effective vaccine against HIV.

Jon Allan, of the Southwest Foundation for Biomedical Research in San Antonio, Texas, has focused on that question for more than a decade, studying not only SIVs, but also simian foamy virus, cancer-causing STLVs and other viruses that have co-evolved with specific African monkey species and have cousin viruses that infect human beings.

He's found that the normal monkey hosts of these viruses can't prevent them from being passed sexually or from being replicated within their bodies. Additionally, he says, the animals' immune systems never make antibodies to destroy the viruses.

Instead, Allan explains, the viruses seem to fall into a state of "benign neglect," inside their natural hosts where a form of "viral quiescence exists."

But when the viruses find their way into other monkey, ape or human species, that state changes to "kill or be killed, or take no prisoners," Allan said. The viruses invariably kill the same types of cells in the new species that they used as comfortable homes in the original host species.

Now, researchers say, science needs to take this finding a step further, determining just exactly which viruses can jump between species and why such viruses tend to turn mean when they make the jump. And the best place to find these answers, they say, is the Congo River basin region of equatorial Africa, where primates are hunted and eaten by humans.

Viruses in the Congo basin are passed from one species to another when animals fight, clawing and biting; when blood spreads during the slaughter; or via blood exposure during the butchering of the meat by humans, and possibly - if there are sores in the gums or mouths of the predator - when the prey is eaten.

Once thought to be an extremely rare event, cross-species viral transmission from African monkeys and apes to humans is now seen fairly frequently, experts say, though it has, thankfully, resulted in very few epidemics.

"It's a bit like Hollywood," Dr. Simon Wain-Hobson of the Institut Pasteur in Paris said at the conference, organized by the Centers for Disease Control and Prevention. "For every star [such as the SIVcpzUSA strain found by Hahn] you've got hundreds of starlets who didn't make it."

Dr. Donald Burke of the Johns Hopkins School of Public Health, meanwhile, suggested that scientists think of "emerging genes, not emerging viruses. Maybe all of these epidemics have lapped on the shores of homo sapiens for a long time . . . now social events have changed, allowing recombination of poorly fit viruses, making them fitter ones that can cross species."

Evolution Of HIV Moves In Uncharted Directions

Now that the global HIV pandemic has raged for two decades, experts who study the evolution of viruses in humans say they're beginning to see trends but don't know yet whether they indicate good news for humanity or bad.

The good news would be that HIV-1, the virus responsible for more than 97 percent of the world's 34 million AIDS cases, is trying to do in humans what it did tens of thousands of years ago in chimps: become a harmless passenger inside our bodies. The bad news would be that HIV-1 is evolving to be more easily spread, or to become a more efficient killer.

"We've seen evolution of more pathologic viruses in monkeys, so we can't let it happen in humans," Dr. Frank Novembre, of the Yerkes Regional Primate Center in Atlanta said rhetorically.

For instance, Dr. Marcia Kalish of the Center for Disease Control and Prevention in Atlanta has been working with researchers in Singapore, studying the genetics of HIV strains found there.

HIV is a relative newcomer to the Asian nation, having originally been confined to a small homosexual population there. In 1991, however, Singapore's heterosexual HIV epidemic took off, primarily afflicting businessmen who visited female prostitutes in neighboring countries.

Most of these heterosexual cases involved HIV-1 subtype E viruses, Kalish said. But those viruses are mutating far more rapidly than has been seen in the United States, where subtype B is prevalent. The mutation is changing the portion of the virus used to infect cells, raising "some very interesting questions about what the subtype E's are diverging towards," she said.

Though Kalish did not expand on that point, the implication was that HIV might be acquiring the ability to infect a broader, or different, range of human cell types.

HIV populations in Central Africa also are changing rapidly, according to Dr. Martine Peeters, of the Laboratoire Retrovirus in Montpellier, France, and others.

Until recently, Peeters said, nearly all HIV-1 in that region was of subtype A. But new viruses have emerged over the past two years that are mixes of subtypes A and G, with some areas - such as Nigeria - showing nearly a third of all HIV-1 types as the A/G combination. Francis McCutcheon of the Henry Jackson Foundation in Rockville, Md., has discovered that most HIV-1 types now infecting patients in Cameroon are such A/G mixes. And in India, Rwanda and Ethiopia another melange virus is emerging, combining subtypes A and C.

"So there is a great underbrush of viral recombinant strains to be worried about," McCutcheon concluded, adding that "recombination is generating a vast, untapped reservoir of complexity of HIV-1."

At the University of Amsterdam, Dr. Jaap Goudsmit and his colleagues have discovered evidence of what he thinks is HIV-1 evolution against combination drug therapy - a process called "drug escape."

In studies of HIV-1 patients, Goudsmit sees that shortly after a patient begins drug therapy, the viruses in the body mutate a single genetic bit of information, forming what scientists refer to as a 215Y mutation. When that mutated virus is passed sexually or through needle use to a partner, it in turn evolves into a new mutant, or 215D.

When that second patient goes on drug treatment the virus evolves again, forming a previously nonexistent form of HIV: a 215S mutant. "And that's multidrug resistant HIV," Goudsmit said.

"So the whole bottom line in the therapy era is you get one-step mutants evolving," which he says means that use of drugs to treat HIV is pushing viral evolution in a unique direction in wealthy countries, where such treatments are affordable.

But in the rest of the world, said Los Alamos National Laboratory scientist Bette Korber, the genetic evolution, particularly in these new A/G and A/C subtypes, is demonstrating "really distinct patterns in functional genes. It's so dramatic, it must be significant." But nobody seems sure of what.

Simon Wain-Hobson of the Institut Pasteur in Paris warned his colleagues that it's too soon to speculate. "The database is too messy to discern any patterns," he insists. "It's simply too complex."

Though no one has evidence specific to the point, Wain-Hobson said, it remains distinctly possible that HIV-1 will evolve into a less dangerous virus, given enough time and millions more human infections. Or it might not.

All of which leaves vaccine production in a serious quandary.

Many African countries are pressuring the United Nations AIDS Program to immediately begin testing of AIDS vaccines that are directed to a single subtype of HIV. But Dr. Saladin Osmanov of UNAIDS in Geneva says that's "short-sighted."

"There may be other variants, coming in and filling in this niche of protection," he said. "If for some reason one subtype slows down, another automatically takes over. I would target for a broadly reactive, broadly protective vaccine."