In early 2013, researchers were stunned to open their program book to paper #48LB at the 20th Conference on Retroviruses and Opportunistic Infections, held in Atlanta, Georgia. The paper was a late-breaking abstract, meaning that the data was brand-new, never published. The abstract, entitled “Functional HIV Cure after Very Early ART of an Infected Infant,” was an exciting development. The abstract’s opening line was: “A single case of HIV cure occurred in an infected adult with a bone marrow transplant,” referring, of course, to Timothy Brown. The case being reported was radically different from Timothy’s. The child had, only 30 hours after being born, received three antiretroviral drugs: Jerome Horwitz’s AZT, 3TC (lamivudine), and neviraprine. On the second day of life, doctors detected HIV in the baby girl, and tested on a weekly basis thereafter. On four successive blood draws, HIV was measured using a sensitive PCR-based assay. The baby was HIV-positive. But, to the surprise of her physicians, the virus slowly disappeared in the baby, becoming undetectable by day 30. Now, two years later, doctors felt confident in calling the child cured.
There was that c-word again. But now Timothy’s influence was so great in the HIV community that physicians were no longer afraid to use the word cure. Unacknowledged but just as influential was Christian, the first Berlin patient, the impetus behind the first clinical trials testing early therapy. Here in this one child lay the combined promise of both Berlin patients. The eradication of the viral reservoir was an experience shared by both Christian and Timothy. The baby had received a very early therapy, right after being infected by the mother, similar to the early therapy Christian received. Because of such an early therapy, the reservoir didn’t have a chance to take hold in the child. However, similar to both Berlin patients, a small amount of virus was detected by ultrasensitive PCR in a subset of blood cells, called monocytes, taken from the baby. Here, then, was the unifying lesson taken from both Berlin patients: We don’t need to eliminate the virus completely. We can create a functional cure for HIV by eliminating enough of the virus, whether it is by early aggressive therapy like Christian received or a gene therapy inspired by Timothy.
Anthony Fauci, director of NIAID, believes that early therapy, such as this baby received, is the path to a cure. Speaking about the promise of this kind of therapy, he says, “Children will be the first group to be cured.” This is a powerful statement coming from Fauci, who is notoriously guarded about making such claims. Fauci says he’s a scientist, and therefore, “I don’t jump out of my pants for anything.” Despite his scientific skepticism, an important quality for any person who holds such influence among researchers and policy makers alike, Fauci says, speaking of Timothy, “Just having a person who is cured galvanized a lot of enthusiasm.” Once again, sometimes it’s the influence of the story that means more than the data.
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In April 2013, a twelve-year-old boy at the University of Minnesota Medical Center, Eric Blue, received an infusion of cells that looked an awful lot like Timothy’s. These cells are hematopoietic stem cells like those Timothy received, but this time, instead of coming from a stranger’s bone marrow, they came from a baby born into the world. These stem cells originated from cord blood, the blood collected from the umbilical cord and placenta when a baby is born.
Hematopoietic stem cells, the progenitors that form all the cells of our immune system, are found at high concentrations in cord blood, ten times higher than in bone marrow. Better still, unlike obtaining stem cells from bone marrow, which requires a surgical procedure, cord blood stem cells are found in the discarded by-products of childbirth. And, while bone marrow cells must be matched exactly between donor and recipient, cord blood cells don’t have to be, because the cells are more primitive than those extracted from adult bone marrow. The primitive nature of cord blood cells also means that the procedure is less risky than bone marrow transplants; patients receiving cord blood transplants are less likely to suffer from graft-versus-host disease, the deadly disease in which transplanted cells attack the host’s body.
Scientists estimate that the chance of finding a matching bone marrow donor with the Δ32 mutation is 1 in 10 million. Because cord blood doesn’t have to be perfectly matched to a patient’s blood, it’s far simpler to find a donor with the Δ32 mutation. This is exactly what researchers did. The young boy received chemotherapy and radiation in an attempt to destroy his cancer and HIV-riddled immune system. They then infused the cord blood cells naturally resistant to HIV. Researchers hoped that this boy would become like Timothy, cured of both his cancer and HIV in one fell swoop. An hour after the boy received the mutant cord blood cells, Timothy gave him a call to wish him luck and give him some advice: “Make sure as soon as you are able, get out of bed and do some exercise, go do what you love, go play some basketball.”
Lead researcher on the study John Wagner, put the procedure in perspective, saying, “There are patients with HIV and leukemia out there today who are waiting for such a breakthrough. But for those with HIV alone, a success in this patient would compel the scientific community to find potentially safer strategies, such as genetically inducing the variant in the patients’ own marrow stem cells.”
Sadly, on July 5, two and a half months after his transplant, Eric passed away. The boy developed graft-versus-host disease, the same disease that came close to taking Timothy’s life. While cord blood transplants are less likely to develop graft-versus- host, any bone marrow transplant is risky. Eric’s death underlines the fact that transplants such as these should only be performed in those who require it for their cancer. His case, despite its tragic ending, has inspired physicians in other parts of the globe to try HIV-resistant cord blood transplants in those patients suffering from both cancer and HIV. However, if we’re going to cure HIV in those without cancer, we have to find safer ways to translate Timothy’s success.
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After Christian’s case received mass attention in the late 1990s, and the subsequent clinical trials based on his therapy failed, the field became wary of the early therapy approach to treating HIV. Despite this warranted skepticism, one researcher remained committed to finding a cure: David Margolis. Margolis graduated from Tufts University School of Medicine in 1985, then stayed at Tufts for his residency. At a time when HIV was taking over hospitals across the Charles River in Boston, Margolis felt insulated from the epidemic at Tufts. He was eager to treat HIV-positive patients; they just didn’t have any. That enthusiasm led him to a fellowship in infectious disease at the NIH. There, he was thrown into the fire of HIV medicine. It was a field like no other, giving the young physician the opportunity of applying molecular biology to clinical medicine.
Despite the foibles of those early therapy clinical trials, none of which were able to replicate Christian’s unique experience, Margolis was unique in the HIV community for pursuing the eradication of HIV. At a time when it wasn’t popular to talk openly about a functional cure for HIV, Margolis was persistent.
Similar to how Jessen pursued an experimental cancer drug to eradicate the virus before the reservoir could take hold, Margolis was pursuing a parallel strategy. He was interested in a group of cancer drugs called histone deacetylase inhibitors. These drugs work by altering our control over our own DNA. DNA is wrapped tightly around proteins called histones. Because our DNA is in such long, unwieldy chains, we need to wrap them around these histones to keep them organized. Similar to how a garden hose is wrapped around a holster in the garden, histone deacetylase keeps the DNA wound around the histones. It’s the presence of this enzyme that lets us unwrap the DNA so that information from the gene can be copied and transcribed by the cell. This enzyme is key to how we use our genes.
Cancer researchers postulated that by inhibiting this enzyme, they would fire up the tumor-suppression gene, a gene that, just as it sounds, protects the cell from cancer. This hypothesis was correct: vorinostat, developed by Merck, was the first such inhibitor to be approved by the FDA for use in cancer in 2006.
HIV researchers such as Margolis took note of this use of this kind of inhibitor. Margolis had been working with this class of inhibitors since 1996 when he first discovered how the anticancer drugs interact with latent HIV. As we have seen, the challenge with eradicating HIV from the body is that the virus can hide in our DNA. When it does this, it’s called a latent virus because, although it isn’t easily detectable, it provides a continual source of virus, essentially a reservoir that standard antiviral drugs aren’t able to shrink. Even after a person has spent decades on antiviral drugs with no detectable virus, once they stop taking the drugs, the virus comes back. Thanks to the viral reservoir. Margolis believed that histone deacetylase inhibitors had the potential to root out the virus hiding in our DNA, just as it woke up the tumor-suppressor gene in cancer. By unwinding the DNA, the drug could uncover the virus hiding within. It was the early 2000s and vorinostat was not yet available. The only inhibitor like it that was available was valproic acid, a drug used to treat seizures and mood disorders.
In 2004, Margolis enrolled a pilot study of four patients who consented to taking the unusual therapy twice a day for three months. Margolis and his group then quantified the amount of HIV in the resting T cells. These immune cells that aren’t actively dividing represent the biggest challenge to eradicating the virus. If Margolis could get them to release HIV, he knew he was on to something. Three of the four participants had a sizable reduction in the latent viral reservoir, on average 75 percent. Margolis and his colleagues made a splash in the HIV community and in the popular press when they published these results in The Lancet in 2005. But the excitement was short-lived; the promising reduction in the viral reservoir faded. Eight months after first receiving valproic acid, the reservoir was back. Like so many eradication attempts before it, valproic acid worked better in theory than it did in patients.
Many scientists faced with such disappointing data would have given up on histone deacetylase inhibitors, but not Margolis. The problem, he reasoned, was finding the right drug. He turned his attention to a different inhibitor known to have a potent effect on multiple classes of the enzyme: vorinostat. It was a drug he had long been interested in but was only recently available to test in humans. Unfortunately, vorinostat isn’t as benign as valproic acid. Vorinostat had the ability to cause mutations in DNA, which can possibly lead to cancer. Getting the FDA to allow Margolis to test the drug would require three years of convincing.
In a packed conference room at the 19th Conference on Retroviruses and Opportunistic Infections, in Seattle, Washington, in 2012, attendees eagerly awaited the results of Margolis’s vorinostat trial. The room was characterless, like any conference room, anywhere in the world. But inside, the crowd was electrified. They knew what was coming. For months, HIV researchers had been gossiping about Margolis’s trial and its promising results. Now the results were to be announced in the late-breaking abstract. The conference room couldn’t hold the throng anxious to hear the results; attendees spilled out into two overflow rooms.
Margolis’s vorinostat results were small but impressive. Margolis had 6 participants. Those 6 HIV-positive men had been given only a single dose of the drug, for the FDA restricted its use. Given these constraints, the community wasn’t expecting what followed. In all 6 men, the reservoir of virus in the resting commander T cells increased, on average fivefold. It was a sign that the drug was releasing the latent virus hiding in the T cells. In a press release put out by the university at the time, Margolis said, “This proves for the first time that there are ways to specifically treat viral latency, the first step toward curing HIV infection.” His results were echoed by those of Sharon Lewin, a researcher from Australia, who found similar safety and efficacy results in her small trial of vorinostat. Researchers hope that the promise of Christian’s cure can be fulfilled in this new but similar eradication strategy.
Margolis, who now has positive results in 8 patients, has convinced the FDA to allow him to test vorinostat on a larger scale. In an ongoing clinical trial, study participants will be given the drug three times a week for eight weeks.
“Cancer, diabetes, multiple sclerosis, you can have any of these diseases but they don’t make you the ‘other’ in the way that HIV does.” Margolis’s patients still ask him, “When is there going to be a cure?” It is as if no one had ever been cured of HIV.