An Elegant Defense Page 15

Four years after Magic’s revelation, the Food and Drug Administration approved a drug called saquinavir. This was the first protease inhibitor.

  Protease is the enzyme in HIV that helps the virus mature once it leaves the nucleus of the cell it has infected. If the enzyme gets inhibited, the virus doesn’t mature. The virus doesn’t spread. The immune system remains intact. The patient doesn’t die.

  “This is some of the most hopeful news in years for people living with AIDS,” said Donna Shalala, then secretary of health and human services, a federal government cabinet position.

  The inhibitor was part of a broad strategy that had been emerging aimed at defeating HIV by hitting it at various points in its “life cycle.” For instance, the first major drug had been azidothymidine, or AZT, which was approved in 1987. AZT interferes with the enzyme that causes the retrovirus to transform from RNA to DNA.

  On its own, AZT had some effectiveness and some side effects. It also could lead to a drop in neutrophils, those critical immune system cells. It could cause anemia, which is a drop in the red blood cells that carry oxygen.

  Together, AZT and a protease inhibitor led to a significant increase in CD4 cell counts. (If you want to geek out, values of CD4 cells rose by 30 or 40 cells per milliliter of blood, a significant figure when the amount in a healthy person is 800 cells per milliliter of blood. Better yet, the CD4 count didn’t drop.)

  It was a turning point in the battle against HIV.

  By 1997, the death rate due to AIDS had dropped 47 percent. AIDS fell out of the top ten causes of death in the United States, plummeting from eighth to fourteenth.

  But it wasn’t the answer to what was happening with HIV. Rather, the drug was like a somewhat effective antibiotic or vaccine. It didn’t explain why some people seemed to be able to fight it themselves. This deadly disease left some people untouched.

  A key insight came from Patient 1.

  This man was a hemophiliac, meaning his blood didn’t clot. Bad news, of course—when you can’t clot, bleeding is prolonged, even indefinitely, and you can die without treatment. To counter this rare genetic condition, the man had received regular infusions of the protein that helps blood clot. One of his infusions was contaminated with HIV, long before it could be tested for.

  “Patient 1,” said Dr. Mark Connors, a Philadelphia native who had come to the NIH after medical school and pediatric training and fallen in love with pure research. An NIH colleague came to him in 1994 and said, “Dr. Connors, we’ve got this highly unusual patient.”

  The hemophiliac was in his twenties, and he had HIV but no viral load, the term for how much of the virus coursed around inside a person. With HIV, the viral load typically took a fascinating path. Initially, it would spike so that there were a million copies of the virus in each milliliter of plasma. (One patient was studied whose load spiked to 5 million copies.) Huge numbers. Then, however, the viral load would typically fall sharply during a chronic phase of the illness and then spike again as death neared.

  The hemophiliac had little viral load. The guy wasn’t sick.

  With the benefit of hindsight, this might look inherently interesting, but Dr. Connors and others weren’t so sure. There could’ve been a number of factors, including the simple possibility that the man had gotten a weak version of the virus.

  Dr. Connors was put in charge of figuring it out.

  Enter the mice.

  The researchers at the NIH did a nifty trick by injecting the hemophiliac’s cells into an immune-deficient mouse. They stripped out the mouse’s immune system. The reason for this is that, as you now know, if the mouse had an immune system, it would have rejected the human cells as foreign. Now they had a mouse infected with replicating versions of Patient 1’s cells—all kinds of cells, white cells, red cells, other cells.

  The mouse didn’t reject the human cells, creating a kind of living laboratory. Lo and behold, the mouse didn’t get HIV. Again, this seemed important but raised the possibility that the hemophiliac’s version of HIV was weak, not necessarily that the hemophiliac’s cells were fighting the illness. Incidentally, as you might’ve inferred, the mouse ultimately died a horrible death because the human cells reacted against the mouse cells, so-called graft-versus-host disease.

  Then came the Bingo Experiment. They gave mice the hemophiliac’s cells, but this time they tinkered with the T cells. They did so by giving the mouse an antibody—that highly specific protein involved in detection and defense—that would pick up and attack the CD8 T cells of the hemophiliac. In other words, the mouse wouldn’t reject all of the foreign cells, just a little piece, a key section of the T cell.

  This time, the mouse contracted HIV. That pretty much nailed it. This was, is, a CD8-dictated mechanism. Bingo. HIV would win, unless the body’s T cell foot soldiers unleashed an immediate effective response.

  Subsequent studies in monkeys reinforced the discovery. The studies showed that the primate immune system, when artificially depleted of CD8 cells, lost control of the virus.

  Bob Hoff, and a handful like him, helped tie the evidence together.

  26

  The Prime

  In March 1998, Dr. Migueles, the young AIDS investigator from Miami, had finished his medical training and began a round of interviews to see where he’d go next. He knew he wanted to continue to work on HIV. He had lots of opportunities. But only one possible miracle awaited him. He discovered it—where else?—on the eleventh floor of Building 10 at the National Institutes of Health. So much great research had been done here, by Dr. Fauci and Dr. Dinarello and others, not just on HIV, but on the basic science of the immune system and its connection to a myriad of diseases.

  Now Dr. Migueles came to interview for a fellowship. He met that March day with Dr. Connors in a small office that, coincidentally, Dr. Connors had inherited from Dr. Fauci. During the interview, Dr. Connors told Dr. Migueles that he and his team had started looking at a small group of HIV patients who hadn’t seemed to be getting sick.

  The interview took an enthusiastic turn. “That’s unbelievable. That’s got to be where the answer lies,” Dr. Migueles said.

  “I know, right? Isn’t that amazing?”

  Dr. Migueles told Dr. Connors about a patient he’d taken care of at Georgetown whose symptoms just didn’t add up. “This woman comes in, she’s incredibly sick for six days. Then she’s fine. I was like, am I losing my mind?”

  Dr. Migueles suspected the woman belonged to some curious, if not revelatory, group of HIV patients who were defying everything known about the disease. But he didn’t have a name or context for what that might be. Dr. Connors had collected a handful of these people and started testing their blood. Were they just having a delayed onset of symptoms, or was something else going on?

  Dr. Migueles was offered the job and took it. He wanted to work with Dr. Connors to cure HIV.

  At that time, the so-called AIDS cocktail was having an impact on the death rate. That was relatively good news, particularly in the United States, where, as I mentioned, AIDS had dropped out of the top ten causes of death.

  Still, every minute of 1998, an estimated 11 men, women, and children got HIV. Overall, 5.8 million people worldwide were newly diagnosed with AIDS, bringing the total of people living with the disease to 33.4 million, according to UNAIDS, a United Nations organization cooperating with the World Health Organization. Deaths globally in 1998 were 2.5 million, the most in any year, and the total dead from the epidemic was just shy of 14 million. The disease continued to be focused in developed nations but was increasingly spreading to emerging countries, with 70 percent of the people infected that year in sub-Saharan Africa, UNAIDS reported.

  “The epidemic has not been overcome anywhere,” the report reads. “Virtually every country in the world has seen new infections in 1998 and the epidemic is frankly out of control in many places.”

  And even where science and medicine had made great strides, with the cocktail, there were powerful side effects. The drugs incr
eased patients’ vulnerability to diabetes, for instance. Perhaps this was not surprising, given the delicate balance of the immune system; strengthening it to fight HIV meant triggering echoes that, in this case, seemed to cause the body to attack itself and its ability to process sugars. Yes, it beat dying, but there was also nothing fun in developing a “buffalo hump,” which was the nickname given to a condition common with the cocktail that caused fat deposits to rearrange in the body, notably in the shoulders.

  One HIV-positive man, Brian Baker, began to develop a buffalo hump. He’d been diagnosed in 1993 when he was thirty. He worked in a record store and as a disc jockey. He lost fat in his cheeks, the layers of skin on his lips fell off. His moods swung. He had to go off the meds for a while. He was alive at least.

  Soon he’d meet Bob Hoff, and a romance would bloom. In the meantime, Bob felt like a cornered man, watching all his friends die, waiting for his own shoe to drop.

  “I felt that at any point in time I was going to be dead,” Bob reflected. This was his experience of the mid- to late 1990s: inspecting his body for purple spots and his mouth for white fungus. He couldn’t make sense of what was happening, and his confusion was combined with mounting survivor’s guilt. “I would meet people and it was just unbelievable, they all died. I’d make new friends and all those guys died.” He stopped wanting to go out at all. He likened it to the way his dad’s friends had died in World War II, and before that, to how his mother’s friends had died of the Spanish flu.

  “Pandemics come along and kill people and wars kill people, and this was my turn at the barrel,” he said.

  Why not him?

  He had a theory as to why he was still alive. Maybe, he thought, it had to with a healthy diet and with a colonic cleansing routine he did regularly. He thought that maybe his immune system had gotten so distracted by this process that it couldn’t be overtaken by HIV. It didn’t make a lot of sense, but what did or could?

  By now his blood had long since been collected by the NIH; recall that he’d gone there years earlier with dying friends. He wasn’t yet marked for study, though. He was merely one of the people that the NIH kept an eye on, given that researchers didn’t yet know if he was simply destined to get sick. He’d go in every six months and give some more blood. He kept on living, asymptomatic.

  Then he got a call to come in to meet with Dr. Migueles.

  When Dr. Migueles was first hired at the NIH, he joined a meeting with the other investigators trying to figure out what they hoped to learn from guys like Bob Hoff. Dr. Migueles was the junior guy in the room, and he made a list of all the possibilities that might explain the molecular mechanism that made immune system marvels of these mortal men. It was needle-in-the-haystack work.

  Given all the complexities of the immune system, a plethora of possible pathways might be saving these men. Could it be that they had gotten a weakened strain of the disease? Could it be that they had immune systems trained previously through some particular set of circumstances of diseases, or that they had a peculiar way of binding to the disease or communicating about it to other parts of the immune system?

  Dr. Migueles made a long list of options, and the team set about trying to eliminate the irrelevant ones. They needed the vaccine or medicine that would bolster the immune system, and they were up against the clock. People were dying.

  When he first met Bob, Dr. Migueles was working his way down that list of possibilities. It was December 10, 2007. Bob figured to offer further evidence.

  “You have an immune system that is constantly fighting,” Dr. Migueles told him. Bob was a “long-term non-progressor,” in the language of the field. It should’ve been great news, at least to him personally, but Bob felt malaise. “There’s no joy in being a survivor.”

  And, Bob recalled, he was told, “This is not a get-out-of-jail-free card.” Bob was cautioned that he could still die if his immune system faced another assault—from, say, hepatitis, shingles—another debilitating attack that required his immune system’s full attention.

  Dr. Migueles said that he wanted to start studying Bob’s blood to try to look for markers that might help explain Bob’s own survival and help lead to a cure, a real cure. Of course Bob agreed.

  At the time, Dr. Migueles told Bob that he had a theory that Bob had better-responding CD8 T cells than other people. He told Bob: “Your immune cells respond more vigorously to the virus than the cells of other people.”

  But this alone was essentially unsatisfying to Dr. Migueles and other researchers. To find a cure, to dismantle AIDS, they needed to know not only what the immune system did, they needed to know how it did it.

  In the late 1990s, Dr. Migueles and fellow researchers at NIH—along with other researchers around the world—found a major clue that distinguished Bob and others like him.

  Many so-called elite controllers, patients like Bob who keep HIV at bay, have a gene that impacts the way the immune system recognizes foreign invaders. Specifically, they share a genetic variant called HLA-B57. HLA stands for human leukocyte antigen. That’s the human version of MHC that Dr. Doherty and others discovered years earlier and for which they won a Nobel Prize. The HLA is essential in helping the human immune system distinguish between things that are self and things that are foreign. In Bob and other elite controllers, this key gene, B57, seemed different. In the first study of elite controllers, eleven of the thirteen had this gene. By comparison, only 10 percent of the population as a whole have B57.

  This was a very powerful discovery. It essentially identified one likely genetic underpinning of an immune system that could fight off this version of a plague—a key piece of DNA for unleashing an effective T cell response to HIV.

  Further, Bob and the other elite controllers weren’t surviving because their virus strain was weak. It was just as potent as strains killing left and right.

  “They don’t harbor wimpy viruses,” Dr. Migueles said. He knew that they were seeing a powerful immune system variation. “This is evidence of what the human immune system is capable of doing. They are alive with infection we thought uniformly fatal but acting as if they have the herpes virus, and the virus is sitting there doing very little.”

  There was a third key discovery. It now appeared that Bob and the other elite controllers had survived likely due to a very specific moment in the interaction between their immune systems and HIV: the first point of contact.

  “The evidence is pointing us to what we call the prime—the priming event. It’s when the immune system first sees virus,” Dr. Migueles said. “We suspect people like Bob start down the road to being an elite controller right at the beginning.”

  These are major revelations, particularly the idea that the way you deal with a disease might well be dictated by this idea of a prime, or first point of contact. The initial response, whether to flu or HIV or a cold, might well echo through the immune system. The right first response could save your life, not that you have particular control over such a thing. However, knowing this can inform the way we build medicines, or study individuals to see their susceptibility to various viruses, say, through genetic testing. Some of this is yet to be foretold by science—but is now within its grasp.

  Indeed, the sum of the work done at the NIH has led to a much deeper understanding of the immune system. Such essential science “has relevance for inflammatory-based disease, autoimmunity, and cancer,” Dr. Migueles said. The papers the scientists have written are seeds of medicines and treatments and, in particular, of vaccine development. The way that elite controllers react is based on a “common pathway” of how our elegant defenses work on a molecular level.

  Dr. Migueles said that intensive study of HIV has helped develop “a flow chart of the multiplicity of relationships” in how the immune system cascade works. “That’s where the treasure chest is.”

  Perhaps the biggest part of the canvas is how this research, along with lots of work from many places, led to the most important conclusion of all.


  “People are no longer dying,” Dr. Migueles said. The cocktail that saves lives, going all the way back to AZT, includes leaps in basic immunology, including those attained by the team at NIH. That work has had to keep going because HIV, like all organisms, continues to evolve, to survive, and to evade detection not just by the immune system but by the drugs.

  “It’s an arms race,” Dr. Migueles maintains.

  Another way to look at this arms race is from a social perspective. “This was a death sentence. People were terrified and nobody cared and Reagan wouldn’t say the word,” Dr. Migueles said. “Their own government had betrayed them. So they took it on themselves to be their own voice.

  “This wouldn’t have been done if they hadn’t mobilized. It was miraculous.”

  They acted in their own defense, a social complement to their immune systems, calling out: We are not alien. We are part of society, we are self!

  That notion has since led to many movements of medical self-empowerment, such as the crowds who walk for breast cancer and the sports figures who mobilize awareness around a particular disease.

  In the end, key takeaways from Bob’s story and key lessons about our collective health come from how we relate to each other on a social and political front. And Bob had his own happy ending. But before I bring his story and medical contributions to a close, I want to fill out the broader scientific picture by telling you about a different group of people, the ones whose immune systems are too powerful.

  Part IV

  Linda and Merredith

  27

  Linda

  Linda Bowman came into the world in March 1960, the second-born in her family, and that status helped define her. Her big sister, Joanne, was two and a half years older. In the race of life, Joanne was Linda’s rabbit—the thing to chase. If Joanne had homework, Linda wanted to do it. Linda excelled at math in particular; she was so good, she had skipped third grade. The larger truth was that Linda could apply herself, loved to do it, had that internal drive that only some have and most don’t.