CHAPTER 11
Calling All Elite Controllers
In 1995, Bruce Walker was a successful physician and researcher at one of the top hospitals in the country. That year, he met a man named Bob Massie, whose genes would take Walker’s lab in a new direction. In his poignant memoir, A Song in the Night: A Memoir of Resilience, Massie recalls Walker’s initial doubt that the healthy man standing in front of him was, in fact, HIV-positive. Massie had been infected by a blood transfusion to treat his hemophilia when he was twenty-two. For the past seventeen years, he had somehow remained healthy, despite the fact that he hadn’t taken any antiviral medications. Massie, who was engaged and wanted to be able to give his fiancée an answer to his medical mystery, was hoping Walker would be able to figure out what was going on inside his body. Walker confirmed that Massie was, in fact, HIV-positive, by an antibody test. It wasn’t clear how he was able to control the virus.
Walker was still interested in how killer T cells, the storm troopers of the immune system, defend against HIV infection. Unlucky for us, HIV takes out the commander T cells, first thing, which means we lose the cells we need to coordinate our immune system. It’s also bad luck for the virus, of course, which just wants to make more of itself. With us dead, it can no longer do that. The fact that the virus kills us is a sign that, evolutionarily, we haven’t coexisted with it very long. With a little more time, we’d have found a better way for us to survive together. Successful viruses don’t kill their hosts; they find a way to flourish within them.
The world is filled with little creatures that favorably live with larger ones. One hundred trillion microorganisms live peacefully within our gut. The white-gray patches on whales are actually small creatures called barnacles, which live happily with the large mammals, as much as a half ton of the animals on a single humpback. In some ways, humans have more in common with HIV than whales do with barnacles. Like HIV, we have a flawed relationship with what we need to live. Like the virus that destroys the cells it needs to survive, we often destroy, by activities such as deforestation and pollution, the very habitat we depend on for our survival. HIV takes out our commander T cells because they express CD4, the protein HIV needs to enter our cells. With the commanders gone, the immune system can’t mount an effective attack: the storm troopers don’t know where they’re supposed to go and whom they need to kill. Without the commanders, the bombers aren’t given the signals they need to drop antibodies that can bind up the virus. Without the commanders, the body is so shaken that it can’t remember if it’s seen the virus before. Even more insidious, HIV takes out the commanders during the asymptomatic stage of infection, before a person even knows he’s infected, when he still feels healthy.
What Walker noticed right away when he looked at Massie’s blood was that, surprisingly, he still had his commander T cells. It wasn’t simply the presence of the commanders that was unusual; it was the fact that these cells were also HIV-specific. The commanders can specifically recognize that a cell is infected with HIV and mount a vigorous response. The army of T cells in Bob Massie was larger than any Walker had ever seen in an HIV-infected person.
By chance, Walker had stumbled onto a patient able to control HIV through the very mechanism on which he was an established expert. It was clear to Walker that he had to figure out how Massie’s commander T cells were preserved. From his early work on HIV and the immune system, he already had a hint. He suspected that the HLA, the genes that govern our immune system, were behind this remarkable control of HIV. The only way to know if the genes were the underlying cause was to find other people like Massie, who controlled HIV in a similar way.
Walker was giving a talk in New York City six years later when the tide turned. The talk was an update on the science of HIV and AIDS, which he was presenting to three hundred physicians and nurses who saw large numbers of HIV-positive people. Walker casually mentioned Massie, who was often on his mind. He asked the clinicians if any of them had seen a case like it. Over half the audience raised their hands. “I must have audibly gasped,” Walker remembers. Here was the answer. If Walker reached out to enough HIV clinics, he could compare the HLA genes among these elite controllers. If they all had some particular gene in common, then perhaps there would be a way to get that gene into HIV patients who didn’t have it.
There was the problem of raising enough money to do even initial experiments. Walker believed there was a genetic tie among elite controllers and that it lay in the HLA genes. But he couldn’t specifically say how that connection worked. No government agency, the typical partner in such research, wanted to fund an experiment that didn’t know what it was looking for. During this frustrating time, Walker had breakfast with Mark and Lisa Schwartz. Mark, an investment banker at Goldman Sachs, and his wife, Lisa, an organic farmer and cheese maker, were funding an effort by Harvard to train African scientists and physicians to work on the HIV crisis. Mark asked Walker what else he was working on. Walker told him about the elite controller project and his difficulty in getting anyone to fund it. Mark and Lisa immediately understood the logic behind the project. That day, they committed $2.5 million dollars to collect samples from elite controllers. Walker then began making phone calls to collaborators around the world.
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This approach to treating HIV, through the individual genetics of those who control the virus, was part of a growing trend. The promise of personalized medicine is that a patient’s genes can inform our understanding of disease, indicate appropriate therapy, and determine likely side effects. As the cost of sequencing a patient’s genes has dropped, our understanding of the intersection between disease and genetics has grown. Currently in clinical trials, we have investigational new drugs that repair the mutant gene responsible for cystic fibrosis. We have drugs capable of targeting specific proteins involved in cancer cell proliferation, as uncovered by genetics studies. The gene therapy field once struggled under the weight of seemingly insurmountable safety issues, suffering a major setback when an eighteen-year-old died in 1999 at the University of Pennsylvania. This resulted in the FDA’s suspension of numerous clinical trials. But today the field is in a renaissance of sorts, with positive data being reported from such wide-ranging clinical trials as inherited blindness, Parkinson’s disease, and inherited blood disorders. The current challenge in genetics-based medicine is that we simply have too much data. It’s difficult to sort through which relationships are important and which are happenstances. For HIV, you would want to find a group of people who all had the same genetically powered machinery that enabled them to control HIV. Researchers had learned of the connection between the mutation known as Δ32 and HIV resistance. But Walker’s genetics study of elite controllers was about to uncover a new way to keep HIV under control.
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Dan Forich lays spread on the hospital gurney, feeling cold and nervous in his thin hospital gown. He flew from San Francisco to Boston to have the procedure: a routine upper and lower endoscopy, in which a thin probe attached to a camera is run down his throat and then another is run up his anus to obtain intestinal tissue samples. It’s a common procedure used to check for polyps and the beginning of intestinal cancers. Forich smiles and shakes his head when asked if he has any questions, but deep down he’s concerned about the anesthesia and what will happen if polyps are found. Mostly, Forich just feels hungry, for the preparation before the surgery meant he has not eaten in over twelve hours, instead having flushed his system with a particularly disgusting liquid he was told was needed to clean his intestines.
Forich has lived with HIV for more than two decades. He’s watched close friends succumb to the disease, and most heartbreaking, he lost his boyfriend, who died from AIDS-related complications. Yet Forich remains healthy and, importantly, has never taken any antiviral drugs.
He is not alone. It is estimated that 1 in 300 Americans and 1 in 100 Europeans diagnosed with HIV will be able to control the virus without medications. In total, about 1 percent of the HIV-positive population doesn’t need to take medication. Within this special group of people who can control HIV are subsets. Elite controllers essentially have undetectable virus in their blood: less than 50 copies per milliliter. Viremic controllers, on the other hand, are those with detectable virus, 50–2,000 copies per milliliter. Both groups are able to control the virus without therapy, although the long-term prognosis is better for elite controllers. Because they carry so little virus, it is nearly impossible for controllers to transmit it. However, the picture isn’t all rosy; viremic controllers will sometimes, unexplainably, after decades of controlling the virus, suddenly slip toward AIDS.
It’s important to remember that even if an elite controller has undetectable levels of virus in the blood, this doesn’t mean there isn’t virus hiding in other tissues. A special tissue called the gut-associated lymphoid tissue, or GALT, which lines the intestines, hosts the vast majority of the body’s immune system. Unlike the blood, where immune cells are free-floating, the GALT forms a dense network of disease-fighting cells.
Because so much of the immune system is concentrated in the gut, this is where the body forms its first line of defense against outsiders. Mucosa-associated tissue lines these battlegrounds at the nose, throat, tonsils, intestine, and urogenital tract. In order to defend the body, the GALT hosts a large number of lymphocytes, which can identify the intruders and mount an attack.
While for most diseases it’s advantageous for all the immune cells to be waiting to pounce, HIV is not so easily defeated. For HIV, this tissue isn’t a threat, it’s a welcome mat. Up to 90 percent of intestinal cells express CD4. In addition, lymphocytes in the gut express so much CCR5 that researchers originally thought the CCR5 receptor was unique to the gut. It’s the perfect place for HIV to infect and take over, ramping up billions of copies of itself that can be spread throughout the body. In addition, the gut is the ideal hiding place for the virus. It can remain dormant in the gut for decades, long after antiviral drugs have wiped out the virus in the blood. For reasons we don’t understand, the virus wakes up and returns to its full force. So the road to defeating HIV has to lead through the gut. Without considering what’s happening in this key part of our immunity, we are doomed to continue harboring the virus and never being able to clear it. This is why HIV researchers ask for so much from HIV controllers and from the Berlin patients. Researchers need to know how they are able to keep the virus in check not only in the blood but in tissues, too.
Besides their ability to control HIV without medications, perhaps what is most remarkable about HIV controllers is their generosity in aiding HIV research. Hundreds of HIV controllers like Dan Forich undergo invasive surgery and long-term testing to help in the fight against the AIDS epidemic, without any direct benefit to themselves. Dan talks about this as he lies on a gurney, about to go into the invasive procedure. When asked why he’s doing it, his answer becomes twisted, turning into a thank-you to the researchers, seemingly oblivious to his own contribution.
When asked what he thinks about the science behind his incredible control of HIV, Dan says, “I don’t know. I guess I’m just lucky.” He has been contributing to research for more than a decade. This is the second time he’s flown across the country to undergo a voluntary and uncomfortable procedure. Yet, despite all these years of exposure to cutting-edge research, no researcher has ever sat down with him and explained how it is that he’s lived with HIV for so long without developing AIDS. Somehow, science has been left out of informed consent. Where Jessen spends time explaining the biology of HIV to his patients, few researchers are able to spend this kind of time with their study subjects. Patients may understand the risk behind the procedure or therapy they receive, but it’s unlikely they’ve discussed the science.
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People like Dan are able to control HIV for such a long time without therapy because of their genetics. We understand this because of the gamble Mark and Lisa Schwartz made on Bruce Walker’s research in 2002. Walker’s wild hypothesis turned out to be right. Elite controllers have special genes that reside in chromosome 6 and encode the HLA, the human leukocyte antigen. HLAs are incredibly diverse in humans. Our individual HLA encodes a set of proteins that are then displayed on the surface of every single one of our cells. These HLA proteins are the equivalent of a secret handshake. If a cell has them, the immune system knows the cell is human. If the cell doesn’t, it will be tagged as foreign and destroyed. This is why, when someone is getting a tissue transplant, whether it is liver cells or stem cells, the HLAs between the donor and the recipient must match. That way the donor cells are recognizable when they get into the body and it’s less likely the transplant will be rejected by the body.
These proteins play a key role in HIV infection as well. When the virus enters the body, it’s eaten up by antigen-presenting cells, or APCs. The APCs digest the viral proteins and then load bits of virus, the antigens, onto the HLA proteins that lie on the cell’s surface. The head on a stake. They then bring the antigens to T cells. Like pieces of a puzzle, the T cell, viral proteins, and APC fit together. The signal the T cells receive from the APC determines the kind of response the immune system will mount. It turns out that, for HIV controllers, the message is loud and clear. The antigens that controllers display are very different from those of people who progress to AIDS. The virus acts as a double agent in HIV controllers, secretly signaling to the T cell that, yes, the threat is real and the immune system has to give it everything it’s got. How HIV controllers mobilize the commander and storm trooper T cells is shown in the illustration on page 108.
It’s not just that HIV controllers tend to have similar HLA genes, although they do. Specific HLA-B genes, such as B*57 and B*27, are found at disproportionately high levels in HIV controllers. This is similar to macaque monkeys; animals that have the HLA Mamu A*01 gene are more likely to control SIV, the primate counterpart of HIV.
How controllers defeat HIV. The virus infects T cells in controllers and those that progress to HIV in the same way. Antigen-presenting cells sense the invader and swallow the virus. Controllers stimulate the production of HIV-specific commander T cells and storm trooper T cells, while progressors can’t naturally mount as strong an immune response.
But it turns out that it’s not the gene that’s truly important. The real difference in HIV controllers lies in the individual amino acids that make up the groove on the HLA protein. The majority of HIV controllers have specific amino acids in this one region on the surface of the APC. Only a few altered letters of DNA make all the difference in whether or not a person can control HIV. So the difference between a person whose body can naturally control HIV and one who cannot goes beyond genetics. The real secret lies in a small section of the HLA-B gene encoding three amino acids. People who have these three amino acids—serine at position 97, methionine at position 95, and tryptophan at position 94—are likely to naturally control HIV through a coordinated immune system attack. Their bodies are able to present a special part of the virus to the T cell, unleashing the full force of the immune system onto HIV.
Sitting on the surface of all the cells in Dan Forich’s body is this handful of amino acids. They don’t give him an advantage in any other disease. In fact, they might make him more susceptible to certain autoimmune disorders such as psoriasis. But what these special amino acids do on Dan’s behalf far outweighs any potential danger they might present. They protect him from AIDS.
A person without this genetic blessing has no inborn mechanism to control the virus. Now that scientists understood the basis of elite control of HIV, how could they translate it into a therapy for those without the special genes?