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Immune to a Plague

A few lucky individuals won't ever contract AIDS: they're genetically immune. And the more we learn about how their genes protect them, the closer we come to protecting all of us.

By Peter Radetsky
Jun 1, 1997 12:00 AMOct 15, 2019 5:50 PM


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The story begins with a mouse. With a bunch of them, that is; a bustling colony of smallish brown field mice scurrying through the grain bins of a squab farm outside Los Angeles in 1979. They were not quite ordinary mice. They happened to carry a gene that protected them against a devastating leukemia virus that was annihilating the rest of the rodents on the farm. This gene, a restriction gene, barred infection by blocking the doorway--the receptor--through which the virus gained entry to the cells it attacked. Denied access, the lethal virus was left futilely hammering at the gate, harmless and vulnerable, to be destroyed in short order by the body’s defenses. In other words, these mice were genetically immune to the disease.  This finding set Stephen O’Brien, a National Cancer Institute (NCI) geneticist who had helped analyze the gene, to thinking: If mice could carry a gene that protected them against a deadly viral invasion, why couldn’t we? In 1979 there was no way to find out, since no comparable human outbreak had come along. But soon enough history offered up an exemplary epidemic: the scourge of AIDS. By 1984 it was known that the disease’s cause was a fiendishly elusive virus called hiv. O’Brien responded immediately.  I rounded up half a dozen AIDS researchers and asked them what they thought of the idea of looking for a human restriction gene. They said, ‘Sounds great, but we don’t know anything about human genetics.’ I rounded up human geneticists and said, ‘What do you think?’ They said, ‘This is a wonderful idea, but we’re scared to work with hiv.’ So I said, ‘Okay, I’m going to try it.’  O’Brien asked physicians across the country to send blood from their high-risk and infected patients to his lab in Frederick, Maryland. They were happy to help. They just sent, and sent, and sent the stuff to us. For ten years people have been sending us blood samples. We now have in the can samples from something like 10,000 patients. For ten years O’Brien and his team have been sifting through this treasure trove of blood for a gene that protects against infection with hiv.  Last August he found it, with more than a little help from his friends. In the space of a year an astonishing burst of revelations by numerous scientists has transformed AIDS research, confirming the reality of genetic immunity to this terrifying disease and offering a realistic possibility of its prevention and cure. Finding the gene, however, involved more twists and turns, more coincidence and serendipity, than O’Brien could ever have anticipated. In fact, finding the gene was mostly the result of not even looking for it.  Back in 1986, when O’Brien was starting to build up his store of HIV blood samples, across the country in San Francisco, University of California virologist Jay Levy was describing some puzzling events involving HIV infection. Levy was not a geneticist; nevertheless, his findings were to provide the first lead in the hunt for the gene.  There was a man who routinely came in to be checked for infection, Levy recalls. We followed him for about five months, and suddenly we could no longer find virus in his blood. We didn’t know what was going on. Finally we decided that maybe he’s still got the virus but we were missing it because there were cells preventing it from coming out. The logical cell was the cd8 lymphocyte.  HIV infects white blood cells, or lymphocytes, called cd4 (after the name of a prominent protein on their surface). The main job of cd4 lymphocytes is to help other immune cells function. By penetrating these cd4 cells and forcing them to churn out new viruses that infect and destroy yet more cells, HIV brings the body’s defense response to a grinding halt. The upshot is AIDS. Part of that defense response involves cells called cd8 lymphocytes--the killer cells and suppressor cells of the immune system. When a virus, such as hiv, infects a cd4 cell, the cell displays telltale markers on its surface. cd8 cells can recognize these cues and punctually destroy the diseased cell, or at least suppress its function. No wonder Levy suspected that cd8s might be at the heart of his patient’s unexpected turnaround.  Levy investigated. We did experiments in which we removed cd8 cells from samples of the subject’s blood. It was really dramatic: virus appeared. Then we put the cd8 cells back in the blood, and the virus went away. And by this time we were seeing this same phenomenon in other people. Pull cd8s out, virus comes out--put cd8s back, virus goes away. But the cd8 cells weren’t actually eliminating the cd4 cells--that is, with the cd8 cells present, the cd4 cells in the sample weren’t dying. Perhaps, he thought, the cd8 cells were producing some substance that suppressed the virus, preventing it from replicating. To test that hunch, he and his colleagues put cd8 cells in a lab dish, covered them with a fine-mesh screen, then spread cd4 cells over the top. The screen kept the cells apart but allowed fluid secreted by the cd8 cells to diffuse upward to the cd4s. Sure enough, the virus disappeared.  For Levy, then, the key to stopping AIDS involved understanding cd8’s role in the tortuous progression of disease. Most people infected with HIV remain healthy for years, until finally coming down with AIDS symptoms, growing weaker, and eventually dying. Levy felt that cd8 cells were the key. The way we tied events together is this: A person gets infected with hiv, and at first the cd8s control the virus. Then for some reason the cd8s lose control, the virus comes out, kills off cd4 cells, and the person goes on to disease.  Not many others agreed. People didn’t believe us, Levy says. I can’t explain why. Maybe because this represented a new idea in immunology. Why would you suppress and not kill? While his colleagues looked on with a kind of bemused tolerance, Levy began a decade’s search for the active substance in the cd8 reaction (he called it caf, for cd8 antiviral factor). He had no luck. It turned out that cd8 cells, like other lymphocytes, were hard to keep alive in the lab, and they manufactured the elusive factor only once in a while, making it hard for Levy to amass enough for study. He was reduced to describing what his factor was not.  I kept saying, ‘It isn’t this, this, this, or this.’ But everyone kept saying, ‘Why don’t you tell us what it is?’ says Levy, sighing. This has been the longest project for me.  It may be that Robert Gallo has found Levy’s factor for him. In early 1995, almost ten years after Levy first described his baffling cases, Gallo--the rambunctious former nci and current University of Maryland researcher who codiscovered hiv--and collaborator Paolo Lusso set out to determine once and for all whether there was anything to this caf business. They, like Levy, were not looking for an hiv-resistance gene, but what they turned up offered the second lead to its existence.  I brought up in a staff meeting that sooner or later we were going to have to look at this crazy story, Gallo says. Levy had been talking about it for a decade. You get suspicious in this modern age when somebody talks for a decade.  Gallo’s huge nci laboratory was ideally set up for the search. From long experience, his team had cultivated a large number of cd4 cells that they could readily infect with hiv, and they had figured out how to keep cd8 cells alive. In December 1995, Gallo and Lusso announced that they had found substances secreted by cd8 lymphocytes that did indeed suppress the replication of hiv. Specifically, they stopped viruses in the blood of individuals who had just been infected--that is, they prevented HIV from establishing a beachhead in the body. There were three of these suppressive substances. They were all members of an obscure family of hormonelike molecules called chemokines, small proteins known to help cause inflammation, presumably by latching onto chemokine receptors on immune system cells and dragging them to the site of injury. Most researchers knew next to nothing about them.  I can honestly say that I had heard of them, but barely, says Gallo. He laughs. A chemokine expert told me that when our paper came out his mother called him. She had heard on npr about these ‘cheezokines’ that Dr. Gallo had found. ‘It’s very important,’ she said. ‘You should work on it.’  AIDS researchers agreed. They rushed to investigate the little- known proteins, in the hopes that they might be used to stop the disease.  Thus the stage was set for lead number three. In a laboratory at the National Institute of Allergy and Infectious Diseases (niaid) in Bethesda, Maryland, biochemist Edward Berger was coming to the end of his own long quest: to understand how HIV enters cells. It had been suspected for over a decade that each time HIV entered a cell, this wily virus co- opted not one but two receptors on the cell surface. One receptor was cd4, the very surface protein that lent the cd4 cell its name. The other was a mystery. For years scientists, Berger among them, had been trying to uncover its identity. By December 1995, when Gallo announced his chemokine discovery, Berger was sure his team had hit pay dirt.  He had found a complicated protein, a Loch Ness monster of a protein, that snaked above and below the surface of cd4 cells seven times-- thus its designation as a seven transmembrane protein. By somehow docking with both it and the cd4 protein, HIV could fuse with cells and infect them. If cells lacked this protein, the virus remained outside. It must be the long-sought second receptor, thought Berger. Because it allowed virus to fuse with cells, he named it fusin.  The virus involved was different from the strain stopped by chemokines, however. Chemokines suppressed viruses encountering the body for the first time. But HIV quickly mutates in the body after infection. Fusin allowed these already flourishing viruses to spread further throughout the body during the late, symptomatic stages of disease. So although fusin was not the end of the story--hiv must have been using some other receptor to enter cells during the early stage of infection, before it had a chance to mutate--it was an important step.  What was this odd molecule? Surely it had a function other than acting as a receptor for late-stage hiv. When Berger and his team sequenced fusin’s DNA, they found that their protein was a relatively anonymous member of a huge family of similar molecules. This family of proteins acts as receptors for extraordinarily diverse chemical processes, says Berger. Receptors for neurotransmitters, receptors for olfaction, taste, sight. There are hundreds if not thousands of individual genes that are members of this family. He pauses. And some of them are receptors for chemokines.  Chemokines--when Berger presented his results at a meeting in February 1996, more than a few AIDS researchers began making unexpected connections. Here were Gallo and Lusso finding that certain chemokines stop viruses from infecting cells in the first place. Here was Berger announcing that fusin, a protein from a family that includes chemokine receptors, facilitated the spread of viruses that had already invaded the body. Chemokines, fusin, hiv--the connection was tantalizing. Could it be that, like fusin, another receptor, a seven-transmembrane chemokine receptor, opened the door to the virus’s initial onslaught? Could it be that chemokines stopped the assault by blocking this as yet unknown receptor? No one was thinking about a protective gene yet, but it sure looked as though Gallo and Berger had deciphered only part of the story.  By March, in Berger’s words, My phone started ringing off the hook. Among those on the line was biochemist John Moore from the Aaron Diamond AIDS Research Center in Manhattan. He was calling to congratulate Berger on his groundbreaking discovery--and to fish for information. Ed is Tyrannosaurus rex, says Moore. He killed the beast. But we weren’t going to let him eat the whole thing. We were going to be raptors clawing at the carcass. Moore and his colleagues were looking hard for a chemokine receptor.  We had read a bit about chemokines, but we knew nothing about seven-transmembrane receptors, Moore says. In the middle of March, I went to a meeting in New Orleans and brought a huge file of reprints with me. It was my crash course, Chemokine Receptor 101. In one of the papers there was a footnote saying that a seven-transmembrane receptor called ccr5 bound one of Gallo’s hiv- suppressing chemokines. That was a critical footnote.  The news intrigued Moore’s colleague Richard Koup. With a postdoc, William Paxton, Koup had been investigating the mysterious case of two gay men who, although long involved in high-risk sexual behavior, had never even become infected by hiv, much less taken sick. Even before Gallo’s announcement, Koup and Paxton had come up with two very interesting pieces of information: that cd4 cells from these men could not be infected by the primary strain of hiv, and that the men made an unusually large amount of chemokines.  Initially we didn’t believe it, Koup says. Then the Gallo paper came out. He was seeing almost the same thing we were seeing. Lights went off in our heads.  Lights also went off in the head of Diamond researcher Nathaniel Landau. When I thought about it, it made sense that chemokines might be the key, he says. By binding to a chemokine receptor, they might block hiv. It just started smelling like the right thing.  What ensued was what Landau calls one of the most fascinating chapters in the development of science. In the space of two weeks in late June, researchers from five different labs independently announced that they had found the coreceptor on cd4 cells that enabled HIV to establish its initial foothold in the body. It was indeed a chemokine receptor. And not just any chemokine receptor, but the very one Moore had come upon in the footnote, the seven-transmembrane protein ccr5--the docking site for the chemokines that Gallo had found instrumental in preventing infection in the lab.  The discovery came from the University of Pennsylvania, from the Dana-Farber Cancer Institute in Boston, from the niaid lab of Ed Berger (who hit the jackpot again), and from two teams at the Aaron Diamond Institute. Koup, Moore, and Paxton led one team, Landau and Dan Littman of New York University’s Howard Hughes Medical Center led the other. All raced each other to be the first into print. You know that you have to work all night, and all weekend, because if you’re not one of the first people in print, you’re nowhere, says Koup. I don’t think there’s ever been a scientific discovery where the data were generated as quickly, and were out in print as quickly, as this. And by so many people. It was just amazing.  Landau agrees. Dan and I were writing our paper as fast as possible, sending it back and forth by E-mail. I was sleeping in my office- -I have a sleeping bag under my desk. We had arranged a courier to transport the paper overnight to the journal Nature in London. He was supposed to come here at three in the afternoon, and we were still working on the paper at two. Then at 2:30 our E-mail system broke down. And the courier showed up. I went crazy, screaming at the computer guy to fix the system. Finally it fixed itself. The manuscript wasn’t in such good shape, but we sent it anyway. He laughs. It was pretty funny when we got the reviews back. One of the reviewers said, ‘Out of 15 authors, couldn’t any of them have proofread this manuscript?’  This white-hot explosion of discoveries revolutionized AIDS research. For one thing, the finding that HIV used ccr5 as a coreceptor reinforced the researchers’ suspicions about how the chemokines might suppress infection. By docking onto the receptor, they might block HIV from doing the same thing.  For another, it explained a great deal about the progression to disease. The virus initially infects cd4 cells via the cd4 protein and the ccr5 receptor. Then, years later, having mutated in the body, it learns how to use another receptor on cd4 cells as well--fusin. And somehow this new route of infection signals a sea change. Once the virus learns to use fusin, cells begin to die off at an alarming rate. People get sick--the symptoms of AIDS appear. And because fusin appears on a wide variety of cells, not just cd4 lymphocytes, these symptoms become many and varied.  For example, we know that fusin is expressed in very high levels throughout the central nervous system and the brain, says Dan Littman. Late in the disease many people get neurological symptoms--AIDS dementia. When the virus adapts to fusin, it might trigger some harmful signal that leads to the destruction of the nervous system, though this is still very speculative.  And now scientists began to glean details of how the virus initially enters cells. Says Moore, The cd4 receptor sticks up from the cell, while ccr5 keeps close to the surface. The virus binds to cd4 like a blimp docking at the top of the Empire State Building. But you need to get it way down to the subway station on 34th Street--that’s ccr5--so the passengers can get off. Otherwise you just have a blimp stuck to the top of the building. The virus and the surface of the cell change shape, allowing the blimp to drop down to the subway station.  Still, however, none of these researchers was thinking about protective genes. Finally that was about to change. We said, ‘Now let’s figure out these exposed-uninfected individuals, recalls Koup. Why can’t they be infected by hiv? Maybe it was because their coreceptors don’t work.  He was right. In August, when he and Landau discovered why, they suddenly found themselves face-to-face with a gene. It turned out that the gene for the patients’ ccr5 receptor was defective. It sported a hole smack-dab in the middle of its DNA. The result was a ccr5 protein so badly deformed that the cell destroyed it instead of displaying it on its surface. No wonder the patients were resistant to infection--without the ccr5 receptor, HIV couldn’t get its genetic material down from the top of the Empire State Building. As with O’Brien’s mice, the defective gene protected them.  Genetic immunity to HIV was a bombshell of a discovery. No one had foreseen it. No one had intended it. It was the serendipitous result of a haphazard succession of seemingly unrelated revelations. But for all the researchers’ excitement, it was still an extremely limited finding. These were just two people. They could be freaks of nature. To determine whether this immunity was authentic and prevalent, many more people would have to be scrutinized. As Koup says, It was time to look at bigger populations.  Reenter Steve O’Brien. For ten years he had been combing through his vast reserves of blood samples, looking with scant success for the tiniest hint of a resistant gene. The discovery of the ccr5 receptor galvanized him. This wasn’t just a hint--it was shout, a bellow, a clarion call. His lab was poised for just such an eventuality. And O’Brien pounced. By August, when Koup and Landau announced their news, O’Brien had already submitted for publication a study of blood samples from some 1,955 high- risk individuals. They included gay men who had unprotected sex, intravenous drug users who shared needles, hemophiliacs who received tainted blood products. This investigation would pin down the truth of genetic immunity to HIV one way or another.  The results were astounding. There is indeed a defective chemokine receptor gene, and it does indeed confer resistance to the virus. Moreover, this genetic immunity is surprisingly widespread. We carry in our cells two copies of almost every gene, one inherited from our mother, one from our father. O’Brien found that one in a hundred Caucasian Americans carries two copies of the defective gene--like Koup’s patients, they are completely immune. One in five Caucasian Americans carries one copy of the mutant gene. Although these people can become infected, typically they stay healthy two to three years longer than those without any copies of the altered gene. O’Brien speculates that the reason may be that they have only half as many ccr5 receptors as is normal. And half as many receptors probably limits the spread of virus and slows down the whole damn thing.  However, the defective gene shows up much more rarely in African Americans, and almost never in native Africans, or Asians. Why not? The answer must lie in the gene’s origin. The resistance gene in O’Brien’s genetically immune mice probably arose during an ancient viral outbreak and came down through the generations to the present day. He suspects a similar origin for this human gene--but with one major difference. It must be relatively new, stemming from a time after the ancestors of the first Caucasians made their way out of Africa.  We’re thinking that the mutation probably took place on the order of 100,000 years ago, O’Brien says. And because of the unusual nature of the mutation--that big deletion in the middle of the gene--we think it probably occurred in just one person. You hardly ever see dramatic mutations like this when you scroll through human genes--natural selection gets rid of them. But not this time.  All of which leads to a knotty question. One hundred thousand years is a blink of an eye in evolutionary terms, hardly long enough for one lonely mutation, by chance, to gradually proliferate until it shows up in as much as 20 percent of a given population. How in the hell did the gene get to be so frequent? wonders O’Brien. Something like that doesn’t just happen by chance. Something jacked it up.  That something might have been a devastating epidemic that killed off much of the population while sparing those carrying the defective gene, which, presumably, protected them. Those survivors, who now made up a large percentage of the depleted population, passed the gene to their offspring. Given that kind of jump start, the gene might have spread to the millions who carry it today. It could have been a prehistoric HIV that came in and wiped out large numbers of Caucasians, says O’Brien. It could have been cholera, flu, bubonic plague. At least a quarter of the people in medieval Europe died from plague. That’s a hell of a selective pressure.  But all that is conjecture. We don’t know anything about bubonic plague and chemokines. We don’t know anything about flu and chemokines. We didn’t even know what a chemokine receptor was until a few months ago. So when I give talks now I get these infectious-disease guys aside and ask them, ‘Does your pathogen use this receptor?’  Meanwhile, the frantic pace of research continues, now with an emphasis on translating these new findings into practical treatments. Levy, who is not convinced that chemokines are the major mechanism in caf, continues to try to pin down his elusive antiviral factor. (Over a decade later, his original patient remains healthy.) Gallo, for his part, is convinced. His team is attempting to demonstrate chemokines’ essential role in protection by injecting them into monkeys and then exposing the animals to virus. If the chemokines succeed in preventing infection, the next step may be to design a vaccine that provokes the immune system to boost chemokine production in the presence of HIV.  Berger and Moore are independently trying to figure out how cell and virus interact, in the hopes of interfering with the process. Their hopes are high because seven-transmembrane receptors, the family to which ccr5 and fusin belong, are so familiar. They have been major targets of drugs for other diseases, says Berger. About a third of the top 40 best- selling drugs target seven-transmembrane receptors. I’m sitting here with an inhaler for my asthma, and that’s targeting a seven-transmembrane receptor. As a result, scientists have a leg up in looking for compounds that block the receptors, so as to block HIV’s access to cells. Landau and Littman are also among those in the hunt.  Littman is trying as well to produce a genetically engineered mouse that displays human ccr5 and fusin receptors on its cells. Such an animal would provide a living laboratory in which to investigate the process of infection and disease. Getting a good animal model is the only way to understand the mechanism of pathogenesis, he says. Besides, even if we understand the molecular processes in the cell much better, eventually we have to confirm anything we do in an animal.  Others are looking into the possibility of providing the protective gene to infected people via gene therapy and bone marrow transplants. It might also be possible to devise a drug that disables the protein that forms the ccr5 receptor. These strategies appear promising because, in the case of ccr5 at least, those who carry defective versions of the gene for the receptor seem otherwise unaffected. In other words, the normal gene appears to play no discernible role in life--we can do without it just fine. It’s as if Mother Nature just handed this gene to us, says Landau. It gives you optimism that you can knock it out without hurting anybody.  And there might be other mutations that block HIV. It’s unlikely that Caucasians are the only ones to have evolved genetic resistance-- people of African and Asian descent probably have their own defense mechanisms. Many populations include uninfected high-risk people, among them many Africans and Asians, and most don’t carry the defective gene. Something else must be protecting them. Landau and Koup are among those looking for what that might be. It could be a tiny mutation, something that’s not obvious, Koup says. This one was too easy. Usually it’s not easy at all.  O’Brien is also searching for protective genes. This isn’t going to be the last gene that gets discovered, he says. I think that by the end of the year we’re going to be able to say that this gene contributes this percentage of protection, that gene contributes that percentage of protection--until we can account for much of the genetic component of infection. Nor does he think that AIDS is the only disease in which protective genes play a role. We can go after other diseases, such as hepatitis, which is a leading cause of deaths from cancer, and prostate cancer and breast cancer. We’re going to pin down some of these hidden genes.  But he might not agree that the process of discovery has been easy. He’s been at it too long for that. There were plenty of people who told me that looking for human resistance genes was likely to fail. They didn’t think there was any evidence for such genes.  So much for that argument.

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