On November 7, 1991, Stephen Migueles, a medical student at the University of Miami, was ironing a shirt and watching the news when one of the world’s greatest athletes, Earvin “Magic” Johnson Jr., appeared on television for a special announcement. Magic wore a dark suit, a white shirt, and a gray tie with a hint of red.
“Because of the HIV virus that I have attained, I will have to retire from the Lakers.”
The eventual Dr. Migueles was riveted, like so many, but perhaps his interest went deeper. Dr. Migueles worked in the AIDS ward trying to stop one of the deadliest viruses ever with the equivalent of Band-Aids.
Dr. Migueles brought extra baggage. He was coming out of the closet. No easy task for him, having grown on up in a Hispanic, deeply Catholic family.
“I knew what I was, but I hadn’t blossomed into my full self, if you will,” he told me. He’d come out to his family and it hadn’t gone well. At the time, his parents were devastated.
Then he was watching the men in the ward die. “I was trying to be true to myself, and I saw people around me who had come out and were proud of who they are and dying because of it. It was a scary crossroads.”
Magic Johnson’s revelation meant something to Dr. Migueles. “He was more mainstream,” Dr. Migueles said, but that wasn’t all. “Most people you learned about who had AIDS were celebrities and seen as dying. Magic seemed to be a little different, seemingly robust. He looked like he was doing great.”
He was lucky, of course. Only days after Magic’s announcement, Freddie Mercury, the operatic rocking lead singer of Queen, announced he had AIDS. He died on November 24, 1991.
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.