Posted by Maria Codina on July 8, 2019 at 5:02 pm
Nobody knew what killed Robert Rayford. The African American boy was just 15 years old when he presented at St Louis city hospital in late 1968, but the medical team drew a blank.
Unexplained swelling in Rayford’s genitalia soon spread throughout his body. Chlamydia bacteria, usually localised at the point of entry, coursed through his bloodstream. A small purple lesion on the inside of his thigh signalled cancer, but of a form usually found in elderly Ashkenazi Jews and Italians, not teenage black boys who had never left Missouri.
The teenager hardly spoke during the 18 months in which he received treatment at three separate hospitals. “He was the typical 15-year-old who is not going to talk to adults, especially when I’m white and he’s black,” one of his doctors would tell the St Louis Post-Dispatch almost two decades later. He told them he had sex with a girl from his neighbourhood, but gave little else away.
Tragically, pneumonia ended Rayford’s young life during the night of 15 May 1969, but his body had been compromised some time before. Illnesses that a healthy body would ordinarily expunge met with no resistance. Rayford’s clinicians, puzzled by his decline, persuaded his family to submit his body to an autopsy and preserved samples for inspection at a later date.
Twelve years later, in 1981, reports surfaced of young men dying from aggressive forms of pneumonia. Many reported the same purple-black lesion found on Rayford’s inner thigh. Most were “active homosexuals” and, like Rayford, many had immune systems so dysfunctional that a common cold could hospitalise them. The disease was Aids. There was no effective treatment, let alone a cure.
In the mid-1980s, a young retrovirologist based at Tulane University in New Orleans tested the samples taken from Rayford’s body. They “contained antibodies to every one of the nine HIV proteins used in the test,” reported the Chicago Tribune in 1987. Rayford’s mother, Constance, had little to add when TV cameras showed up on her doorstep: “He was nothing but 16 years old,” she said, bewildered and visibly upset by her child’s posthumous notoriety.
The findings placed the arrival of Aids in the US more than a decade earlier than popular theories suspected, and afforded Rayford a dubious place in the history of a retrovirus that has since killed more than 35 million people worldwide.
In the US, Aids would bore its way through society’s faultlines, decimating communities of drug users, sex workers, gay and bisexual men, along with African Americans, and wiping out a generation of creative lodestars, including photographer Peter Hujar, artist David Wojnarowicz, dance pioneer Willi Ninja and Hollywood star Rock Hudson. But the bulk of the deaths occurred in sub-Saharan Africa, where fragile health systems, religious opposition to contraceptive provision and stigma helped the virus spread like wildfire, killing millions and crippling fragile economies ill-equipped to combat a pandemic.
Now, 50 years on from Rayford’s death, news of the second patient seemingly cured of HIV has raised great hopes. Modern antiretroviral treatment can already suppress HIV to the point that it has no impact on life expectancy, and even make it untransmittable. Yet the “London patient”, who has been free of HIV for 21 months and counting, offers something more: the hope of freedom from a virus that 37 million people worldwide are living with.
The human body can fight off most viruses. But HIV infects and eventually wipes out the very cells needed to kill it: CD4 T, 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 shed like spores into the bloodstream. More cells get infected, and the cycle repeats. The body, in an attempt to contain the virus, kills infected cells. “Once the CD4 T cells are wiped out, you have no rudder for your immune system,” says Dr Carl Dieffenbach, director of the Division of Aids at the US National Institute of Allergy and Infectious Diseases.
Antiretroviral therapy has saved millions of lives by stopping the virus from replicating and allowing the CD4 T cells to recover, keeping the immune system intact. But it cannot eradicate the virus from the body. That’s because when HIV enters its host cell, it sometimes does something highly unusual: it integrates its DNA into that of the cell. At that point, it turns latent, 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 rebound into 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,” says Dieffenbach.
But on 5 March 5 this year, a breakthrough was announced: a team of UK-based researchers 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 lymphoma, a cancer of the immune system. The only treatment left was intense chemotherapy, followed by a bone marrow transplant containing the stem cells required to rebuild his hollowed-out immune system. That transplant presented an opportunity to treat the London patient’s HIV, too.
Scientists selected a donor with a rare genetic mutation that grants resistance to HIV. When HIV infects its target cell, it does so via a protein on the cell’s surface called CCR5. But the genetic mutation changes the shape of the CCR5, leaving HIV with nothing to latch on 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 succeeded!’” 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 now been in remission from HIV for more than 10 years.
But Brown’s treatment was much more brutal: he underwent full body irradiation, and two separate stem cell transplants, each of which poses a risk of death if the graft doesn’t take. The few other patients who have undergone this form of treatment have either died from the cancer’s return, been killed by the transplant, or had their HIV bounce back.
“The Berlin patient left us wondering whether we need to take a patient near to death to cure HIV,” says Professor Ravindra Gupta, who led the London patient’s team. “Now we know you don’t. You can give much less toxic regimens of chemotherapy. And maybe you can get away with less still.” However, he cautions that reducing the harms of the procedure doesn’t equate to making it safe or viable.
First, it is much too dangerous to administer to people receiving antiretroviral treatment who can already live healthy lives. Second, the stem cell transplants bring their own risks: when grafts don’t take, the body rebels, and can even kill the patient. And third, it relies on finding a donor with the CCR5 mutation who is also a blood match for the recipient patient: “It’s incredibly rare to find that combination of factors,” says Gupta.
For Gupta, perhaps the most valuable outcome of the London patient experiment is not the precise procedure they underwent, but the general proof of concept it provides – ie, that targeting CCR5 may lead to an HIV cure: “Gene editing is the most obvious way of extending these findings,” says Gupta. Gene editing can conjure images of scientists playing God, fiddling with human genetics without concern for ethics or unintended consequences – which has already happened in China. He Jiankui, a Chinese professor, attempted to delete the CCR5 gene from two human embryos, for which he was universally condemned. The long-term effects for the children are still unknown. But the gene editing Gupta moots is different. Editing embryos 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 problem is ensuring the accuracy of the editing. And also, that it would take decades, if ever, to offer a scalable cure.
In the meantime, many other strategies are under development, and two in particular have made headlines in the last 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 neutralise HIV as it passes between cells, stemming its spread. Several years ago, Dr Marina Caskey from the Rockefeller University and her colleagues isolated and began producing these antibodies in their laboratory. In 2017, Caskey stopped the antiretroviral therapy for a selection of HIV-positive patients and injected them with the two antibodies for six weeks. Under ordinary circumstances, the virus would have rebounded rapidly. In this case, it was suppressed for an average of 21 weeks: “The really exciting thing is that one of them is now at almost 90 weeks,” says Caskey. That’s almost 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 still hasn’t rebounded. That means the infusion of antibodies must have led to some longer-term control mediated by the person’s own immune system. “We don’t yet really understand what happened,” says Caskey. There are other caveats, too – some patients had HIV that didn’t respond to the antibodies and, when the antibodies are administered alone, the viruses can develop resistance to them – but it is an exciting discovery.
The other approach, trialled last year, is known as “kick and kill”: first, you wake up the latent virus, so it reveals itself; then, you attack it.
“Latently infected cells appear identical to uninfected cells, so there is no way [for the body] to distinguish between the two,” says Professor John Frater of the University of Oxford. “But if those cells start to express viral proteins on their surface, they become a target.” The trouble with this method is that to cure someone of HIV, it would need to reactivate almost all the virus, but a kick strong enough to do that without harming the patient hasn’t yet been found. “Our participants are well people,” says Frater, “so our threshold for risk is much lower.” The trial failed.
The difficulty and expense inherent in these methods has led some to argue that the money spent on cure research would be better used on providing antiretroviral therapy to the 15 million people who don’t yet have access to it, or on expanding the availability of PrEP, a daily pill that effectively stops HIV acquisition. But “it remains incredibly important that we find a cure,” argues Deborah Gold, chief executive at the National Aids Trust: “We cannot forget that HIV is a global pandemic that continues to be one of the major causes of death in countries across the world. Treatment continues to be expensive and difficult to access. A cure would be a solution.”
Having said that, she wishes people could get as excited by new treatments as they do about possible cures: “We should be as exercised – more exercised, even – about ensuring absolute treatment access for everybody, across the world, because that is the way we will support people living with HIV immediately, and the way we prevent new HIV acquisition right now.”
Because while HIV is no longer a death sentence in rich countries, it remains a burden. For those without free or affordable healthcare, it’s a significant cost; and when stigma abounds, it can still prevent people from living and loving as they see fit. But it is in poorer countries that the epidemic still rages most fiercely. In 2017, around one million people died of Aids-related illnesses, shattering families and hamstringing the economic potential of nations. And when medications are not taken as prescribed, or only sporadically available, there’s a real risk that drug-resistant HIV might one day rear its head.
For Frater, that’s enough of a reason to keep trying: “A cure should never be taken off the agenda.”