The year that definitively shaped the Berlin patients’ cure was 1996. The new antiviral drugs available that year represented a watershed in HIV research. But something else was discovered that year. An odd finding about the effect individual genetics have on controlling HIV that would end up being just as, if not more, important. It was all about the gene known as CCR5. Or rather, it was all about a particular mutation of that gene: delta 32 (Δ32).
In the early 1990s, a small group of gay men in New York City realized that despite having risky sex multiple times with HIV-positive partners, they remained HIV-negative. Some of these men wondered why they remained disease-free, and sought an explanation. Eventually, twenty-five of them made their way to the Aaron Diamond AIDS Research Center on the east side of Manhattan in New York City, where David Ho was the research director. The center is the world’s largest private research center dedicated solely to HIV. This group of men became known as the EUs, for “exposed uninfected,” and were established as a patient cohort at the research center.
In 1996, this group of researchers at the New York City research center published a landmark paper. They had uncovered the reason why these EUs remained uninfected despite their risky behavior. The men had a mutation in their CCR5 gene that causes 32 pieces of the gene to be missing. This came to be known as the Δ32 mutation.
The CCR5 gene encodes the CCR5 protein, and scientists often call it a good-for-nothing gene because its role in the body isn’t essential. CCR5 stands for chemokine receptor type 5. Chemokine receptors sit on the surface of cells and interact with a small family of chemotactic cytokines, collectively called chemokines. Chemokines are like magnets in the body, directing proteins where they need to go. It’s believed that CCR5 directs the movement of proteins around the body in response to chemical signals. Whatever role CCR5 plays, it doesn’t seem to be a very important one. People who have the Δ32 mutation in this gene don’t express the protein in their body and it doesn’t seem to affect their health. If you have the mutation, you probably don’t even know it.
So, although the CCR5 protein seems to play no significant role for us, having it makes us vulnerable to the HIV virus, which uses it to invade our cells. And although the Δ32 mutation also seems to have no purpose, nor causes harm, it protects against HIV. Without a functional CCR5 on the surface of the T cell, HIV isn’t able to get inside. It can’t infect a single cell. When the virus can’t enter the cell, it’s slowly filtered out of the body, unable to hurt anyone. Like an out-of-luck gate-crasher, the virus is locked out.
The good news is that the Δ32 mutation is surprisingly common. It’s found in about 1 percent of Europeans. People who are homozygous for this mutation (meaning that both copies of their CCR5 gene have the deletion) will be resistant to HIV infection throughout their lives. There are also those who are heterozygous for the mutation, meaning they have one mangled CCR5 gene and one normal copy. They express lower than normal levels of CCR5 on the surface of their cells and there is some evidence that even this confers an advantage, slowing the progression to AIDS.
Slowly, researchers around the world were putting together the pieces of how the virus could be controlled. But the question remained. How to turn this knowledge into a therapy capable of saving lives?
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Gero Hütter read the 1996 papers on the Δ32 mutation and HIV with interest. Hütter was in his third year of medical school at Humboldt University of Berlin, Germany. He wasn’t particularly interested in infectious disease or HIV. He was focused on hematology and oncology. He was in his early twenties and spent almost all his time studying. He didn’t enjoy being a student. He had struggled in school before the doctor shortage in Germany pushed him into pursuing medicine. He was already dreaming of what would happen when he finished his medical and research training. He knew he wanted to stay in Berlin. He loved the city and the possibilities it offered for research. It was a competitive environment for academics, and the chances were slim that he would become a faculty member at one of the major medical schools in Berlin. But Hütter knew this was what he wanted, and he was willing to work for it. He daydreamed of working with cancer patients at the Charité hospital, performing exciting research, maybe even curing cancer. HIV was very far from his mind. Nonetheless, when Hütter read the papers detailing how the Δ32 mutation was able to confer protection against HIV, he was struck by the enormity of the finding.
Hütter sat in the medical school library with the journal in his hands and looked out the window at the icy sleet raining down against the glass. It’s so simple, he thought. One mutation and HIV can be stopped. He sat back in his chair. Hütter believed that with such a striking finding and the research coming from David Ho’s lab in New York City it wouldn’t be long before the disease was cured. It seemed obvious that this was a special moment in the history of HIV. Indeed, magazines and newspapers were brazenly declaring the end of AIDS. It seemed that the research findings he held in his hand were likely to be a part of that ending. As he put the copy of Nature back on the shelf, he had little idea how much that paper would mean to him and the care he would be providing to Timothy Brown in the not so distant future.
Meanwhile, Timothy Brown and Christian Hahn grappled with their new HIV diagnoses. Timothy struggled with the side effects of AZT, while Christian was overwhelmed by his complicated drug schedule. Each would face a moment when he believed he was close to death. It turned out that they were not.