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For Kai Brothers, 1981 marked the beginning and the end of a golden era. That was the year he turned 19, moved to San Francisco to join one of the world’s largest gay communities, and met his first boyfriend. “We could walk down the street holding hands and kissing somebody in public. It really was a magical time,” Brothers says. But it was short-lived. “Right after I moved here, we started hearing about people dying.”
Brothers, 52, is sitting in his San Francisco living room with his cat on his lap. A computer technician, he has peppery hair and a carefully trimmed beard. The lines in his face are a reminder of the years that have passed, but he looks healthy.
In the 1980s, Brothers had been donating his blood to a San Francisco blood bank, and sometime in 1986, he recalls, it sent him a piece of certified mail that requested he come in for a test. The blood bank had discovered the human immunodeficiency virus in its stock, and wanted to make sure Brothers didn’t have it. He didn’t go in for the test. “It was the classic state of denial,” he says. “I couldn’t manage it.” Brothers interpreted the letter as confirmation that he was HIV positive.
The anxiety of living in doubt took a toll on Brothers, and in 1989 he went in for an HIV test. It was positive. He believes he contracted the virus from his first boyfriend, who developed AIDS in 1991, and died two years later. That was the darkest period in Brothers’ life. He emptied his 401K, thinking that he wouldn’t live long enough to use it.
Surprisingly, though, Brothers never developed any of the symptoms associated with HIV infection. He continued to play softball, act in local plays, and go to work everyday in a bank. “I’m defying the odds here,” Brothers remembers thinking. “There must be something my body is able to do that is keeping me healthy.”
Brothers now faces a vexing choice—a dilemma that mirrors a quandary for modern medicine.
In 1999, one of Brothers’ friends suggested that he visit Jay Levy, a pioneering AIDS researcher at the University of California, San Francisco. (He independently discovered the HIV virus in 1983.) By then the virus could be seen in the light of evolution. As the virus replicates in the body, it mutates. Some mutations allow the virus to advance in a protracted battle over the immune system.
But sometimes the evolving virus can unlock a response that holds HIV in check. Levy told Brothers he had a drop of luck in his blood. His white blood cells seemed to secrete tiny amounts of a substance that controls HIV. At the time, Brothers was only one of several hundred people, out of tens of millions with HIV, known to control HIV in this way. Levy believes an unidentified protein is responsible, and isolating and harnessing it might allow scientists to produce a revolutionary HIV treatment.
Levy said to Brothers that because his body controlled HIV, and he was in good health, he would be an ideal subject for his study. Brothers agreed on the spot. Since then, Brothers has donated blood to Levy’s study about 150 times. He has also sought out other studies of HIV survivors, and continues to cross the country twice a year to donate blood at the National Institutes of Health in Maryland. “I think about all my friends every time I go,” Brothers says. “I just think, ‘This is for you. And I wish you were still here.’ ”
But today, 26 years after he discovered he was infected, Brothers has learned his luck may be running out. Doctors carefully track two signs that foreshadow AIDS: falling white blood cell counts and a rising viral load, or the amount of HIV present in a blood sample. About a year ago, doctors informed Brothers his white blood cell count was worryingly low (under 400), and his viral load was up around 20,000, considered quite high. Since then both markers have improved some, but his doctors are monitoring him closely.
Brothers now faces a vexing choice. He has never taken antiretroviral drugs, which suppress HIV, and have prolonged countless lives. But if he does start taking the drugs, his body will stop producing the substance that has long protected him. He knows HIV is inching closer to causing him harm, but he also knows he has an advantage that doctors could harness to help others. His dilemma mirrors a quandary for medicine. Do drugs that control viruses today also disrupt evolutionary processes that could benefit us for generations to come?
It took scientists over a decade to grasp how HIV progresses into AIDS—far too long to save most people who were infected as early as Brothers. In the first few days after infection, HIV multiplies at an astonishing pace, hijacking white blood cells, which battle infection, and pumping billions of copies of the virus into the bloodstream. In the 1980s, this incredibly fast pace puzzled researchers. Why would a virus that multiplies so rapidly take so many years to turn deadly? It seemed paradoxical, like looking under the hood of a golf cart and finding a jet engine.
Piece by piece, answers came. Scientists discovered that a few weeks after infection, the immune system reacts by killing infected white blood cells, bringing the virus under control. This marks the beginning of lull that lasts an average of 10 years, during which HIV causes no major symptoms.
The question was why, in the end, the virus always seemed to win out. Researchers realized the progression of HIV to AIDS—the gradual decline in the overall number of white blood cells, and the gradual increase in the number of virus copies—is an evolutionary process. In 1991, when Brothers was still wondering what his body was doing differently, Martin Nowak—an Austrian scientist trained in biology and mathematics—was investigating how and when the virus finally causes AIDS. “I asked myself what would explain the slow timescale of the disease, if there’s such a fast timescale of virus reproduction,” says Nowak, now the director of the Program for Evolutionary Dynamics at Harvard University.
He suspected the answer was evolution. Nowak knew that all copies of HIV contain mutations, which accumulate as the virus replicates over and over. As a result, the virus in an individual’s bloodstream gradually diversifies into distinct variants—a signature of natural selection. In fact, Nowak’s calculations suggested that HIV is one of the fastest-evolving viruses that scientists have ever encountered.
Why would a virus that multiplies so rapidly take so many years to turn deadly?
Nowak wondered if maybe it was no coincidence that HIV evolved rapidly yet progressed slowly; in fact, maybe HIV was stuck spinning its wheels, unable to progress, until it evolved around the immune defenses of its host. This theory would explain why soon after infection the immune system can successfully control the virus, but why years after infection, HIV finally gains traction and becomes full-blown AIDS. Over time, random mutations equip HIV with new ways of attaching to, penetrating, and multiplying within white blood cells.
“The virus is held in check by the immune system of the patient, but evolves away from immune control,” says Nowak. “And that evolutionary process is slow.”
It also has unpredictable effects. The course of HIV through Brothers’ body seems to have roused the antiviral factor. In fact, Levy was surprised when he first discovered it. One day in 1983, he tried and failed to locate the virus in the blood of a patient known to be HIV-positive. Here was the blood, but where was the virus?
This strange absence led him to look closely at a type of white blood cell called CD8+, which normally kill infected cells. Levy says when he extracted the CD8+ cells, he expected he might still not see the virus. “The surprise was that, when we removed the CD8+ cells, the virus suddenly appeared,” Levy says, with a trace of the excitement he felt all those years ago. It was a huge discovery at the time, because scientists hadn’t yet learned that some people have natural defenses against HIV.
The years since have been agonizingly tedious. “We know what the protein does: It blocks the virus from replicating,” Levy says. “It maintains the virus in a silent state, in some people forever. Eventually the infected cells will die. So you could imagine that if you could keep this virus under control for 20, 30 years, you might have a spontaneous cure.”
The problem is he still doesn’t know what the elusive factor is. Identifying the structure of an unknown protein requires a slow process of trial and error, as does the search for whichever gene codes for a particular protein. Using blood from donors like Brothers, Levy has spent 30 years looking for a substance he’s never seen. Some scientists have grown skeptical he will find it.
“Despite a lot of research in that field, nothing has turned up,” says Otto Yang, a professor of infectious diseases at the University of California, Los Angeles, who specializes in HIV infection. Mark Connors, Chief, HIV-Specific Immunity Section, at the National Institutes of Health, strikes a more optimistic note. “When something is unknown like this, I have a tendency not to close the door on it,” he says. “I think it’s worth looking until we find it.”
Levy’s persistence reflects the promise of an anti-HIV protein. Armed with such a substance, he says, “It would be relatively straightforward for a company to produce the protein for therapy, or a drug, that might induce cells in the body to produce it.”
Along with the painstakingly slow lab work, and dwindling interest in his research from funders, Levy faces another obstacle—one that is epitomized by Brothers. Antiretroviral treatment suppresses replication of HIV, which in turn keeps the antiviral substance dormant. The immune system only controls the virus in response to an active HIV infection. “If there’s no virus, it just shuts itself off,” says Levy. That makes it doubly difficult to study the process that keeps patients like Brothers healthy.
Levy admits existing HIV drugs “are pretty remarkable,” and doesn’t advocate that most patients avoid them. He does take the position that the drugs may be over-prescribed, saying it might be better with some patients to let the immune system do its work. Nevertheless, as his blood donors grow older and start antiretroviral treatment, his group of test subjects continues to shrink. Most patients who contract HIV today, Levy explains, are immediately prescribed treatment. The result, he says, is there may come a time in the near future when “you’re not going to be able to study long-term survivors,” as they will likely be on drugs that suppress their natural protections.
Controlling a virus like HIV with drug therapies is major medical progress, and few would deny its benefits. But some virologists and evolutionary biologists consider the potential long-term downside of drug treatments. They see drugs interfering with evolution, which could spread defenses like Brothers’ antiviral protein throughout the human population. As Levy sees it, a gene that codes for an antiviral protein might hide in every person’s DNA, potentially waiting to be expressed and sent to battle against viruses.
Nowak’s research has shown that viruses like HIV can evolve rapidly. But the human immune system also evolves: After many generations, it can develop resilience to disease. When the bubonic plague devastated Europe, people with slight genetic advantages tended to survive, and over time the entire population of survivors evolved resistance against the plague.
Left unchecked, HIV could cause the same evolutionary process. A genetic predisposition—like the one responsible for controlling the virus in Brothers’ blood—would equip part of a population with stronger defenses against viruses. A gradual process of natural selection would then amplify the genes and shore up those defenses. “If a virus really devastated a community, and you had a few people left that survived, there’s a good chance that they would pass on resistance,” says Levy. People and pathogens evolve together.
Douglas Richman, the director of the Center for AIDS Research at the University of California, San Diego, describes the process as an “arms race” of co-evolution. Although Richman is in the camp that questions Levy’s tenacious research, he agrees that evolution shapes the immune system’s defenses. In the long term, as mutations create genetic diversity in both hosts and pathogens, natural selection may lead to stronger viruses, but also tougher immune systems. “Over the course of tens of thousands of years, each of the two—the virus and the survivor—end up being able to deal with each other better,” says Richman. Pathogens gain better weaponry, but our bodies can acquire better shielding.
Medicine can tamper with this evolutionary process. It can redirect viral evolution. Look no further than drug resistance, scientists say, which emerges when diseases evolve around the mechanisms of treatments. Levy, in fact, worries that HIV treatments will, in the long term, produce “resistant viruses like you saw with antibiotics.” Medicine can also affect the evolution of the human immune system. It could ultimately prevent the spread of natural defenses throughout a population, as both naturally resilient individuals and patients who start treatment would be likely to pass on their genes.
Today Brothers remains torn over whether to start treatment or remain a devoted research subject, waiting and hoping that research will help others. For the past 25 years, he says, it’s been easier for him to cope with his HIV status, “knowing you’re involved in something bigger than yourself.” He adds, “I don’t feel like I’ve given everything I can. I want to be there when they find something and leverage it for other people. I want to be at the party at the end of it all.” At the same time, Brothers admits, “It’s my priority to be healthy and alive more than anything else.”
Survival is everything, for both humans and viruses. But one of the things that makes us human is our desire to share survival with each other. It’s in our blood.
Daniel A. Gross is a writer and radio producer based in Boston. Twitter: @readwriteradio
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