No one knew what killed Robert Rayford. The African American boy was only 15 years old when he showed up at the St. Louis city hospital in late 1968, but the medical team was baffled.
An unexplained swelling in Rayford's genitals soon spread throughout his body. Chlamydia bacteria, usually localized at the point of entry, were coursing through his bloodstream. A small purple lesion on his inner thigh indicated cancer, but of a kind typically found in elderly Ashkenazi Jews and Italians, not in Black teenagers who had never left Missouri.
The teenager barely spoke during the 18 months he received treatment at three separate hospitals. “He was a typical 15-year-old boy who wasn’t going to talk to adults, especially when I was white and he was Black,” one of his doctors told the St. Louis Post-Dispatch nearly two decades later. He told them he had had sex with a girl from his neighborhood, but didn’t say much more.
Tragically, pneumonia claimed Rayford's young life on the night of May 15, 1969, but his body had been compromised for some time. Diseases that a healthy body would normally fight off showed no resistance. Rayford's doctors, baffled by his decline, persuaded his family to have his body autopsied and to preserve samples for later examination.
Twelve years later, in 1981, reports emerged of young men dying from aggressive forms of pneumonia. Many reported the same purplish-black lesion found on Rayford's inner thigh. Most were "active homosexuals," and like Rayford, many had immune systems so compromised that a common cold could land them in the hospital. The disease was AIDS. There was no effective treatment, let alone a cure.
The findings placed the arrival of AIDS in the U.S. more than a decade earlier than popular theories suspected, and gave Rayford a dubious place in the history of a retrovirus that has killed more than 35 million people worldwide. In the mid-1980s, a young retrovirologist at Tulane University in New Orleans tested samples taken from Rayford's body. They “contained antibodies against each of the nine HIV proteins used in the test,” the Chicago Tribune reported in 1987. Rayford's mother, Constance, had little to add when television cameras appeared at her doorstep: “He was only 16 years old,” she said, bewildered and visibly upset by her son's posthumous notoriety.
In the US, AIDS exploited societal failures, decimating communities of drug users, sex workers, gay and bisexual men, along with African Americans, and wiping out a generation of creative barons, including photographer Peter Hujar, artist David Wojnarowicz, dance pioneer Willi Ninja, and Hollywood star Rock Hudson. But the majority of the deaths occurred in sub-Saharan Africa, where fragile health systems, religious opposition to the provision of contraception, and stigma helped the virus spread like wildfire, killing millions and crippling fragile economies ill-equipped to combat a pandemic.
Now, 50 years after Rayford's death, news of the second patient apparently cured of HIV has generated great hope. Modern antiretroviral treatment can already suppress HIV to the point where it has no impact on life expectancy, and can even render it difficult to transmit. However, the "London patient," who has been HIV-free for 21 months and counting, offers something more: the hope of being free from a virus that affects 37 million people worldwide.
The human body can fight off most viruses. But HIV infects and eventually eliminates the very cells needed to kill it: CD4 T cells, the coordinators of the body's immune response. When the virus invades CD4 T cells, it hijacks their internal machinery and begins making thousands of copies of itself, which are released as spores into the bloodstream. More cells become infected, and the cycle repeats. The body, in an attempt to contain the virus, kills the infected cells. "Once the CD4 T cells are eliminated, there's no rudder for your immune system," says Dr. Carl Dieffenbach, director of the AIDS Division at the U.S. National Institute of Allergy and Infectious Diseases.
Antiretroviral therapy has saved millions of lives by preventing the virus from replicating and allowing CD4 T cells to recover, keeping the immune system intact. But it cannot eradicate the virus from the body. This is because when HIV enters its host cell, it sometimes does something very unusual: it integrates its DNA into the cell's. At that point, it becomes dormant, seeding itself in hiding places throughout the body, where it remains inactive and undetectable, immune to antiretrovirals, but creating a reservoir from which it can recover in a full-blown infection without warning. “All you need is one intact virus, somewhere in the body in a CD4 cell, and at some point it’s going to wake up and spread.”
But on March 5 of this year, a major breakthrough was announced: a team of researchers based in the UK had successfully treated a man, identified only as the "London patient." They declared his HIV in remission for 18 months and counting. The London patient was diagnosed with HIV in 2003, but in 2012 came a second diagnosis: advanced Hodgkin's lymphoma, a cancer of the immune system. The only remaining treatment was intensive chemotherapy, followed by a bone marrow transplant containing the stem cells needed to rebuild his depleted immune system. That transplant also provided the opportunity to treat the London patient's HIV.
Scientists selected a donor with a rare genetic mutation that confers resistance to HIV. When HIV infects its target cell, it does so through a protein on the cell surface called CCR5. But the genetic mutation changes the shape of CCR5, leaving HIV with nothing to attach to. The London patient's immune system was rebuilt with HIV-resistant cells, and the virus was eliminated from his blood. "My reaction to the news was, 'Finally! It's about time someone had a success!'" says Dieffenbach. It's only the second time the procedure has worked: the first was Timothy Ray Brown, sometimes known as the "Berlin patient," who has been in HIV remission for more than 10 years.
But Brown's treatment was far more brutal: he underwent full-body irradiation and two separate stem cell transplants, each carrying a risk of death if the graft fails. The few other patients who have undergone this form of treatment have either died from cancer recurrence, from the transplant itself, or from HIV relapse.
“The Berlin patient left us wondering whether we need to bring a patient to the brink of death to cure HIV,” says Professor Ravindra Gupta, who led the London patient team. “Now we know we don’t. You can give far less toxic chemotherapy regimens. And perhaps you can get away with even less.” However, he cautions that reducing the harms of the procedure does not equate to making it safe or viable.
For Gupta, perhaps the most valuable outcome of the London patient experiment isn't the exact procedure they underwent, but the general proof of concept it provides: that targeting CCR5 can lead to a cure for HIV. "Gene editing is the most obvious way to extend these findings," says Gupta. Gene editing can conjure images of scientists playing God, tinkering with human genetics without regard for ethics or unintended consequences—something that has already happened in China. A Chinese professor attempted to remove the CCR5 gene from two human embryos, for which he was universally condemned. The long-term effects on children are still unknown. But Gupta Moots' gene editing is different. Embryo editing affects every cell in the future adult, and those changes are passed on to future generations; editing cells in an adult does not. The main challenge is ensuring the accuracy of the edit. And also, that it would take decades, if any, to offer a scalable cure. First, it's too dangerous to administer it to people on antiretroviral therapy who are already able to lead healthy lives. Second, stem cell transplants carry their own risks: when grafts don't take, the body can react and even kill the patient. And third, it relies on finding a donor with the CCR5 mutation who is also a match for the recipient: "It's incredibly rare to find that combination of factors," says Gupta.
Meanwhile, many other strategies are being developed, and two in particular have made headlines in the past year. The first involves antibodies: Y-shaped proteins produced in response to foreign substances in the blood. Like the treatment for the London and Berlin patients, this approach took people with natural resistance to HIV as its starting point. These people, known as elite controllers, produce antibodies that can neutralize HIV as it passes between cells, halting its spread. Several years ago, Dr. Marina Caskey of Rockefeller University and her colleagues isolated and began producing these antibodies in their lab. In 2017, Caskey stopped antiretroviral therapy for a selection of HIV-positive patients and injected them with the two antibodies for six weeks. Under normal circumstances, the virus would have quickly rebounded. In this case, it was suppressed for an average of 21 weeks: “What’s really exciting is that one of them is now at almost 90 weeks,” says Caskey. That’s nearly as long as the London patient.
What's puzzling is that the antibodies have long since faded from that person's blood, but the HIV virus hasn't yet returned. That means the antibody infusion must have led to some long-term control mediated by the person's own immune system. "We still don't really understand what happened," Caskey says. There are other caveats, too: some patients had HIV that didn't respond to the antibodies, and when antibodies are given alone, viruses can develop resistance to them, but it's an exciting discovery.
The other approach, tested last year, is known as "kick and kill": First, you awaken the dormant virus, so it reveals itself; then, you attack it.
“Latently infected cells look identical to uninfected cells, so there’s no way [for the body] to distinguish between the two,” says Professor John Frater of Oxford University. “But if those cells start expressing viral proteins on their surface, they become a target.” The problem with this method is that to cure someone of HIV, you need to reactivate almost the entire virus, but a kick strong enough to do so without harming the patient has yet to be found. “Our participants are healthy people,” says Frater, “so our risk threshold is much lower.” The trial failed.
The difficulty and expense inherent in these methods have led some to argue that the money spent on cure research would be better used to provide antiretroviral therapy to the 15 million people who still lack access to it, or to expand the availability of PrEP, a daily pill that effectively prevents HIV transmission. But “it remains incredibly important that we find a cure,” argues Deborah Gold, chief executive of the National AIDS Trust: “We cannot forget that HIV is a global pandemic that remains a leading cause of death in countries around the world. Treatment remains expensive and difficult to access. A cure would be a solution.”
Having said that, he wants people to be just as excited about new treatments as they are about potential cures: “We should be just as practiced, even more practiced, about ensuring absolute access to treatment for everyone, everywhere, because that’s the way forward. We will support people living with HIV immediately, and we’ll focus on preventing new HIV acquisition right now.”
Because while HIV is no longer a death sentence in wealthy countries, it remains a burden. For those without free or affordable healthcare, it represents a significant cost; and where stigma abounds, it can still prevent people from living and loving as they see fit. But it is in the poorest countries where the epidemic remains most virulent. In 2017, around one million people died from AIDS-related illnesses, devastating families and crippling the economic potential of nations. And when medications are not taken as prescribed, or are only available sporadically, there is a real risk that drug-resistant HIV could one day resurface.
For Frater, that's reason enough to keep trying: "A cure should never be taken off the agenda."
By: Edward Diffonde and Thomas Graham https://www.theguardian.com/society/2019/jul/02/cure-for-aids-hiv-related-death-virus