Portland researcher Louis Picker could be on the brink of a cure, and this year will be crucial to his quest.
The bodies of young men arrived in the morgue of Boston’s Beth Israel Hospital emaciated, displaying the ravages of a phenomenon that had only recently been named.
Blood-filled red and purple lesions riddled the corpses’ skin. Creamy white patches of oral thrush covered their mouths and throats. Louis Picker, in 1982 a 26-year-old pathology resident, suited up with full-body protective layers over his scrubs to perform the autopsies. Inside these bodies, the doctor found organs invaded by tumors and lungs heavy with infection.
“Everybody suspected it was some sort of virus, and that it was catching,” Picker recalls, “but nobody knew what it was.” Some had called it GRID—“gay-related immune deficiency”—because rare diseases, brought on by failing immune systems, suddenly seemed to cluster in the nation’s gay communities. The name that stuck, “acquired immune deficiency syndrome,” was coined that same year. Picker had come to Boston fresh out of medical school at the University of California–San Francisco. As the young med student completed his studies, a skin cancer called Kaposi’s sarcoma and a pneumonia caused by a fungus emerged in San Francisco’s gay community, both related to the collapse of sufferers’ immune systems. “For the most part, it was uniformly fatal, and there was quite a bit of hysteria,” Picker says.
Early in his training, Picker was drawn to the study of the immune system—“a complicated, finely tuned dance that came about by evolution,” as he puts it—and how it keeps us alive in a sea of pathogens. AIDS, which robs otherwise healthy adults of these natural defenses, fascinated him. “Here was a disease of the immune system that appeared right in front of my eyes when I was trying to figure out what to do in life,” he says.
In 1985, Picker published his first paper on AIDS and its cause, which had been discovered not long before: human immunodeficiency virus, or HIV. He spent the next decade investigating how T cells, the soldiers of the immune system (and HIV’s target) operate in the body. Every so often he would hear that a former classmate from San Francisco had died of the disease.
In fact, the career of the Los Angeles native entwines with the history of one of the planet’s most lethal infectious killers. Since the days when Picker would scrub down after autopsying Boston’s first AIDS victims, billions of dollars and countless hours have been invested in research, while an estimated 39 million people have died from AIDS-related causes globally. Like the rhapsody of immune cells that work together to fight off infection, scientists around the world have worked for decades to solve the many riddles of HIV and AIDS. Picker is just one character in a worldwide epic. But right now, he and his research team at Portland’s Oregon Health & Science University believe they’re onto something big.
On a recent afternoon Picker, 59, sat in a sun-drenched conference room at OHSU’s West Campus in Beaverton, home to his 26-staffer lab and the rhesus macaques on which their work depends. The immunologist, dressed in his characteristic black jeans and button-down shirt, sounded confident but far from nonchalant as he explained his ambitious vision of a vaccine to prevent and cure AIDS: “I think within 15 years we’ll have both.”
No one would have made this claim a decade ago. AIDS vaccine research has been riddled with setbacks. (In 1984, when US Secretary of Health and Human Services Margaret Heckler announced that researchers at the National Cancer Institute had identified HIV, then called HTLV-III, she expressed hope for a vaccine within two years.) Meanwhile, a major effort for a full-fledged cure—a therapy that would rid the infected of the virus—never really got off the ground, hampered by a lack of critical scientific understanding and funding, and perhaps rendered less urgent by the development of antiretroviral drug therapy that has allowed many people with HIV to live longer. In 1994, AIDS was the leading cause of death for all Americans aged 25 to 44. Today, because of the antiretroviral therapies, many Americans have come to regard AIDS as a chronic illness instead of a death sentence. However, the Centers for Disease Control and Prevention reported in September that about half of the 1.2 million HIV-positive American adults don’t take antiretrovirals, and more than 14,000 Americans with AIDS still die every year.
“The AIDS vaccine field has been kind of a disaster,” says Guido Silvestri, chief division officer of microbiology and immunology at Emory University’s Yerkes National Primate Research Center. “There has been a huge investment of funds, and very little to show so far.”
HIV does present some particular challenges. Vaccines typically train the immune system to attack specific targets, or antigens. But HIV mutates constantly, even within one infected person: the target never stops moving.
“It’s not like influenza, where we can get a different shot ever year and be pretty close to what is circulating,” says Wayne Koff, chief scientific officer of the International AIDS Vaccine Initiative. In the 31 years since HIV was first identified, only four potential vaccines have advanced to human trials. Three of them failed outright—and may have even increased infection rates. Then a large trial in Thailand dealt a surprise: 32 percent efficacy against HIV infection. The results, published in 2009, weren’t good enough to bring that vaccine to market, but they reenergized vaccine research.
Around the same time, the case of Timothy Brown, an HIV-positive Seattle-born man living in Germany, jolted to life the stalled research for a cure. Two bone marrow transplants for leukemia eliminated HIV in the now-famous Berlin Patient. (Brown’s doctor found a donor with two copies of a rare genetic mutation that produces resistance to HIV.) Brown went off his AIDS drugs after his first transplant; eight years later, he’s still HIV-free. But a bone marrow transplant—an invasive, dangerous, and expensive last resort for a person who will otherwise die from cancer—isn’t a realistic option for most of the world’s millions of HIV-positive people. “It’s an experiment, not a solution,” Koff says.
Still, the scientific community took notice. The biggest impediment to a cure is that once a person is infected, a reservoir of HIV always lies dormant in the body. Because it’s not active, this stealth infection is invisible to both the immune system and AIDS drugs. Periodically, some of this latent virus reactivates. Antiretroviral drugs, which first came on the market in 1987, can then fend off these attacks, but take an HIV-positive person off the pills, and the infection will come roaring back. If latent HIV can be wiped out, one way or another—as clearly happened in Brown’s case—it means that the virus isn’t as invincible as it has seemed.
By the mid-’90s, Picker worked at the University of Texas Southwestern Medical Center at Dallas. An infectious agent in the herpes family called cytomegalovirus (CMV) caught his attention as a potential factor in HIV research. CMV is widespread—an estimated 50 percent of people in the developed world will contract CMV by the time they’re 40, and it’s ubiquitous in the developing world. For the vast majority of us, it’s basically harmless. Once a person is infected, CMV stays in the body for life. And—critically—it sparks an enormous immune system response that never stops: in most people with CMV, the body devotes a full 10 percent of its T cells to fighting it. “CMV was different from just about everything else,” Picker says.
All vaccines mimic an infection to prompt the body to prepare for a fight. The best mimic for an HIV infection would be a weakened HIV that could prime the immune system without causing disease. But because HIV mutates so quickly, there’s too much risk that even a weakened strain could “heal itself” and cause a real infection. AIDS vaccine researchers therefore genetically engineer bits and pieces of HIV into less dangerous viruses. Picker was the first to recognize that CMV was uniquely suited for this task.
At this point, he was installed in a comfortable and stable position in Dallas, where one of his jobs was studying specimens from AIDS patients. “The studies I was doing were great,” he says now. “But I realized that it was like looking at the stars—you can’t do anything about it.” He thought he could develop a CMV-based vaccine, but he’d need to test on animals—specifically, nonhuman primates.
Picker did enjoy some standing in the AIDS research world—he’d developed a test to measure T cells specifically dedicated to battling HIV, for instance. But unlike the field’s best-known researchers, he had not made his career in an HIV lab. “I didn’t have a lineage to depend on,” he says. “I had to make my own name starting from scratch. But if I was going to do academia and science, I needed to make the commitment and take the risk of failing.”
In 1999, he quit the Dallas job and came to OHSU, home of the Oregon National Primate Research Center, one of eight such labs in the country. Here he could work on an AIDS vaccine with Jay Nelson, head of OHSU’s Vaccine and Gene Therapy Institute and one of the world’s leading experts in CMV. But after the initial start-up money the university gave him ran out, Picker would be living grant to grant. He’d also stop working directly with patients—probably forever. At OHSU, he’d be focusing solely on research, staking his career on his ability to do the difficult science needed to eradicate a disease that has eluded its pursuers for decades.
Picker set out to prevent AIDS, not cure it. In 2006, he and his team began vaccinating macaques against SIV, the monkey version of HIV. The researchers placed bits of SIV genes inside weakened CMV, hoping the macaques’ immune systems would then mount their natural immediate, large-scale response to CMV. “The immune system will make a response both to the CMV genes and to the SIV or HIV genes that will be in the same flavor, so to speak,” Picker explains. This approach contrasts sharply with that of most HIV vaccine projects, which typically focus on generating antibodies to block infection. Instead, Picker’s method aims to provoke T cells to prevent an infection from progressing to disease. Two years after he inoculated the first group of monkeys with the CMV-based vaccine, he exposed them to SIV.
In 2013, Nature reported Picker’s surprising findings: not only were most of the macaques able to control SIV, but over time their immune systems completely killed off the virus. It was the first evidence of monkeys eliminating the AIDS-causing virus from their bodies. Says Koff: “Louis straddles the prevention and the cure. The most intriguing thing about his vaccine is that the responding animals appear to clear the infection.”
Picker’s vaccinated monkeys are initially infected. But it’s a very low-level infection compared to the normal course of the disease—a small blip instead of a huge spike. In contrast to the typical course of SIV or HIV, which replicate at breakneck speed and overrun the body’s T cells, the bolstered immune system quickly manages this infection, rendering it undetectable in the blood within a matter of days. Remarkably, about a year in, even the most sensitive tests turn up no trace of the virus in tissues where it would normally be present. In the meantime, the monkeys don’t get sick. Today, 64 out of 119 inoculated animals are cured or on their way to being cured.
By all accounts, Picker is curious, determined, and—perhaps most crucial for AIDS vaccine research—creative. Picker’s biggest show of creativity has been his use of CMV to pump up the immune system to fight off AIDS. “Louis’s idea of using the cytomegalovirus has been very innovative,” Silvestri says. “It’s a persistent virus, highly immunogenic, mildly pathogenic in most cases, and can be modified.”
As Picker explains it, “The reason we think it works is because CMV generates these large immune responses at the body’s beachheads, all of the time. They are there at the portal of entry, where the pathogens come in, and they are at all the possible places the pathogens can spread.”
Although there’s no guarantee the results will translate to humans, many in the field are cautiously optimistic that Picker’s immune innovation could be, at the very least, one component of an effective AIDS vaccine. “The model he’s used in primates is very vigorous,” says Robert Seder, who studies vaccines for infections like HIV, tuberculosis, and malaria as chief of the cellular immunology section at the National Institute of Allergy and Infectious Diseases.
If his vaccine is successful in humans, Picker says, “The person who’s protected would have an infection which they wouldn’t notice. They wouldn’t get sick, and it would be cleared.”
In 2008, while attending a conference in Cape Town—where, as in much of sub-Saharan Africa, HIV is rampant—Picker met South African journalist Belinda Beresford. When the two married 10 months later, he became father to her adopted son, who had lost both his biological parents to AIDS. The teenager—one of six children in their blended family—now attends high school in Portland. This connection infuses Picker’s work with a personal drive beyond his scientific ambition. “This is still a terminal illness if you’re poor,” he says. Of the more than 35 million people infected with HIV, shockingly few—only 37 percent—have access to lifesaving antiretroviral drugs. According to the World Health Organization, 1.2 million people worldwide died from AIDS in 2014, including more than 150,000 children.
And while the modern drugs are a godsend for those who can get their hands on them, they’re not perfect. Due to the latent reservoir of HIV, people on antiretrovirals still have a chronic low-level infection that causes inflammation and premature aging. Among many other side effects, AIDS drugs themselves can lead to other serious health problems, like heart disease, kidney disease, and osteoporosis.
Meanwhile, about one in eight HIV-positive Americans doesn’t even know he or she is infected. People who are HIV-negative and at high risk for infection can take a protective drug called Truvada, but must take it daily and see doctors every three months for HIV testing and refills. “It becomes a compliance issue and a cost issue,” Seder says. The US reports 50,000 new HIV cases every year; in Oregon, an average of 260 new cases are diagnosed annually, with more than 100 of those in Multnomah County. Worldwide, it’s estimated that around 2 million people become infected with HIV each year.
The only way to stop this epidemic is to prevent new infections and cure the existing ones. “In this interconnected world, we are more at risk of infectious diseases than ever,” Picker says. “They are going to come back if you don’t get rid of them completely and you don’t keep your vigilance up.”
Based on Picker’s monkey study, in 2014 the Bill and Melinda Gates Foundation awarded his team and OHSU $25 million. The project’s first human study is slated to begin in late 2016. If he can raise enough money—he estimates he’ll need something like $250 million—Picker intends to lure the leading minds in the field to Portland to start a center for HIV cure research at OHSU. With roughly 10 principal investigators, a staff of hundreds, and a dedicated facility for various arms of the research, he would then aim to lay the groundwork for an HIV cure within a little over a decade.
In June, OHSU announced that it had successfully raised $1 billion for cancer research, half from Nike cofounder Phil Knight and his wife, Penny. Picker wants to play in the same league. “If they spend even half that billion dollars wisely,” he says, “OHSU will be a major global force in cancer. That’s the goal here.”
So far, betting on his scientific prowess and CMV seems to have paid off for Picker. “It’s one of those few cases where you have a lovely idea that actually seems to work,” Silvestri says. “Louis’s vaccine is the leading candidate for a preventive AIDS vaccine, and one of the most promising candidates for a therapeutic AIDS vaccine.”
There’s still a lot of difficult work to be done. Picker must show that he can weaken CMV enough that it doesn’t make anyone sick, and that he can elicit the same immune response in humans as he did in monkeys. Only then will he be able to test the vaccine’s effectiveness in humans as prevention or cure. “Advancing into people is not a small step,” Koff says.
He must also protect more subjects. Why more than 40 percent of the monkeys did become infected is a key question. Picker or other researchers must reactivate the virus’s latent reservoir so the immune system can recognize it and fight it off. And they must find and breach the “sanctuaries” in the body, places where the immune system can’t reach latent HIV even after the virus reactivates. (In a paper published in Nature Medicine in January, Picker reported an important biological sanctuary for latent HIV, the B cell follicles of the lymph system.)
Still, Picker believes his vaccine could provide what’s known as a functional cure. Even if it doesn’t wipe out every HIV-infected T cell in the body, it could lower the viral load enough for the immune system to handle it. Given time, HIV-positive people who get the shot could go off their meds without getting sick. Ever.
It would be an epochal achievement. “Being part of either a cure or a vaccine would be wonderful, because it would bring me full circle,” he says. “From being there at the very beginning when the epidemic began to watching the devastation both in this country and through my wife’s eyes in sub-
Saharan Africa—to get to the point where it’s eliminated would be fantastic.”
Even if his AIDS trials fail, Picker believes that tuberculosis, malaria, herpes simplex 2, hepatitis B, even cancer—“other scourges of mankind,” in his parlance—also make promising targets for CMV-based vaccines. Meanwhile, Picker has helped to overturn the conventional wisdom that HIV and AIDS cannot be conquered.
“It’s always nice when you have solid evidence to change dogma,” he says. “That’s new knowledge, and that’s what we’re here for.”