The year was 1998 when Joel Blankson encountered a patient he would never forget. Blankson was working in the HIV clinic at John Hopkins School of Medicine, Baltimore, when an HIV-positive woman in her mid-40s arrived for some routine tests.
Blankson gave her a PCR test, intending to prescribe a newly developed combination of medicines called antiretroviral therapies to suppress the infection, and prevent her developing Aids.
But to his astonishment, the test came back negative. He ran it again, thinking there must have been an error, but the outcome remained the same.
“Despite being HIV-positive, this woman had an undetectable viral load,” says Blankson. “It was the first time I’d seen anything like it.”
Since the early 1990s, similar case studies had begun to emerge of patients who tested positive for HIV, but displayed no symptoms, and were later found to have extremely low levels of the virus in their bodies. The general consensus among the medical community was that these were freak incidents, and the patients were fortunate enough to have been infected with a faulty strain of HIV, which contained mutations preventing it from replicating itself.
But Blankson was not convinced. He found himself wondering whether in some cases, there might be something special about these people that enabled their immune system to suppress HIV. Over the following decade he ran a series of experiments to test this idea.
“We collected samples from a group of these patients, and in a third of them, we managed to amplify the virus so we could study it in the lab,” he recalls. “We found it could replicate itself beautifully in a test tube. We sequenced the whole genome and didn’t find any major mutations. It showed that the virus was perfectly fine. It was the patients that were special, not the virus.”
More than 20 years on, we now know that a small proportion of HIV patients can naturally suppress the virus, and thus avoid developing symptoms, without requiring medication. In some cases, they can do this for decades, even though they have HIV genomes woven deeply into their chromosomes. Scientists call these people elite controllers, and while they make up less than 0.5% of the 38 million HIV-infected people on the planet, they represent the forefront of research into the disease.
The concept of viral control exists for almost all infectious diseases, with asymptomatic Covid-19 patients being another example of elite controllers. For most common viruses such as the Epstein-Barr virus, which is present in more than 90% of people around the world, the majority of people are controllers, and it is only a small proportion of vulnerable individuals who cannot suppress it. However, HIV is a particularly exceptional case. “With HIV, this is very different since only a minor fraction of people can naturally control the virus,” says Nicolas Chomont, an HIV researcher at the University of Montreal. “It is clear that there is something unique in their immune system that allows them to control HIV. Unlike for Epstein-Barr, HIV controllers are the exceptions, not the rule.”
The reason why HIV elite controllers are so interesting is that while antiretrovirals can help the other 99.5% of HIV patients suppress the virus, these drugs have to be taken for life, and are toxic to the body. It is common for patients to develop liver damage and even heart disease, and if they stop the therapy, reservoirs of HIV genomes hiding out in various cells and tissues spring to life again, flooding the bloodstream within weeks.
But understanding how elite controllers manage to keep HIV at bay may yield a wealth of new treatment possibilities. From vaccines that can boost the immune response in people newly infected with HIV, to gene therapies that can help put the virus into a permanent deep sleep, these approaches aim to share the secrets of elite controllers with the rest of the HIV-infected population.
The Esperanza patient
Five years ago, Natalia Laufer – an HIV specialist at the INBIRS Institute in Buenos Aires who has followed elite controllers for 20 years – was attending an infectious diseases conference when she was approached by two doctors who had encountered a particularly unusual patient in the northern Argentinian city of Esperanza.
“She had been exposed to HIV, as her previous boyfriend had died from Aids, but she had an undetectable viral load,” says Laufer. “So we started to follow her. We sent samples to our collaborators in Sydney, and they were unable to find any trace at all of HIV DNA or RNA.”
Intrigued, Laufer contacted scientists at the Ragon Institute in Boston, a centre that has conducted the world’s largest study of elite controllers. Last month, after combing through more than 1bn of the Esperanza patient’s cells, they concluded that the virus had been totally eradicated from her body. Along with a Californian woman called Loren Willenberg, it makes her the second person ever to have been spontaneously cured from HIV.
Previously the only other people ever to have been cured from HIV were Adam Castillejo and Timothy Brown, who both underwent experimental bone marrow transplants primarily to treat their, respectively, lymphoma and leukemia, which replaced their entire immune system with that of someone with a genetic mutation making them resistant to HIV. But this method is risky and takes an extreme physical toll on the patient. While it has worked twice, it has also failed on many occasions.
The fact that these two elite controllers have been able to completely eliminate the virus from their bodies has given many HIV researchers renewed hope of eventually finding a cure. “It is a nice proof of concept that the immune system, under very particular circumstances, cannot only control HIV but may be able to eradicate it,” says Chomont. “But there are still many unknowns. How can we reproduce such an efficient immune response, how long should it last to significantly reduce the amount of persistent HIV, and is it different if the immune response is induced rather than natural?”
While there remain many mysteries about how elite controllers get HIV under control – in part because there are so few of them, and because scientists tend to encounter them only once their body has already tamed the virus into submission – we do have a few clues.
Part of their secret begins in their genes. Approximately 65% of elite controllers carry a particular variant of the human leukocyte antigen B gene, which is located in the major histocompatibility complex region, a part of our DNA that controls the adaptive immune response to pathogens and other threats.
While HIV usually easily wins its battle with the human immune system, the Ragon Institute has found that the presence of this variant means that T cells – immune proteins that attack cells infected with HIV – in elite controllers are particularly equipped to destroy the virus. A 2019 study showed that elite controller T cells are particularly skilled at breaking down amino acids in HIV, which undermine its ability to replicate.
But it isn’t just about T cells. Blankson believes that the reason elite controllers are able to suppress HIV so effectively is that they attack it on multiple fronts. Other immune cells, known as natural killer cells, are primed to respond especially quickly to viral attack, and he suspects that these cells play a role in shutting HIV down before it can cause widespread damage. “We found a couple of cases of patients who were acutely infected, we studied the immune response during that early period, and we showed that they had natural killer-cell responses,” he said. “It takes T cells a couple of weeks to develop an antiviral response. Natural killer cells are effective from day one.”
Last year, a fascinating study in Nature revealed the full effects of this potent immune response. It enables elite controllers to rapidly kill most of the HIV reservoirs, and lock down the few remaining traces of the virus in remote corners of the chromosome where its genes can’t be turned on, otherwise known as gene deserts. Because of this, HIV is essentially rendered dormant, and in cases like the Esperanza patient, it appears to die off altogether.
A permanent sleep
In 2011, Beatriz Mothe, an infectious diseases specialist at the IrsiCaixa Aids Research Institute in Catalonia, decided to try to incorporate the growing amount of information on elite controllers into a therapeutic vaccine programme. While most vaccines prevent individuals from getting a particular disease, Mothe’s aim was to develop a jab that can be administered to anyone who is HIV positive, stimulating an immune response that controls the virus indefinitely, enabling them to stop taking antiretroviral treatment.
While there have been a number of previous attempts to do this, all of which have failed, Mothe suspected that it might be possible to learn from studies of how elite controllers’ T cells successfully target specific locations on the HIV virus. Over the past 10 years, she and her collaborators have been designing a vaccine that could stimulate T cell responses in any HIV patient to attack these particular viral regions.
The latest results appear to be particularly promising. Mothe cautions that the vaccine is still in early stage clinical trials, but data presented at a virtual conference last month showed that it allows some HIV patients to pause antiretroviral treatment for more than five months, and still maintain very low viral load.
“It’s been a long journey,” she says. “It is going to be very challenging to recapitulate the elite control phenomena, but our recent data suggests that we can partially modify HIV specific responses in a way that contributes to better HIV control.”
But while elite controllers suppress HIV in the very early stages of infection, recreating the same effect in people who have already been living with the virus for many years or decades is highly challenging. Mothe is aiming to combine the vaccine with other therapies such as targeted antibodies to create a similar situation where the virus is being attacked on multiple fronts.
One of the limitations with a vaccine is it relies on the body’s own T cells, which naturally wane over time, allowing HIV to spring to life again. Because of this, other scientists are exploring immunotherapies such as CAR T cells – artificial T cells that have been genetically altered so they are hyperaware of HIV – which can patrol the body indefinitely, eliminating any signs of viral reactivation. Scientists refer to this as a “functional cure” – HIV is still present in some cells, but it is kept permanently at bay.
“I think that a functional cure, where patients no longer need to take antiretroviral therapy, will certainly be easier to achieve than a complete eradication of the virus,” says Warner Greene, director of the Gladstone Centre for HIV Cure Research.
In the longer term, Greene believes that it may be possible to combine CAR T cell therapy with gene therapies, which can identify HIV genomes in cells and silence them, preventing them from reactivating. “A consortium of about 15 different scientists think the way forward is what’s called ‘block and lock’, where you try to silence the virus, and put it into a permanent sleep, making it into an inactive piece of DNA,” says Greene. “So you identify the virus clones that keep trying to reactivate, and then just as a backup, you administer CAR T cells, and have them circulate, in case there’s any spontaneous activation in any of those clones that were put to sleep.”
Putting this idea into practice is still a little way off, but through understanding the secrets of elite controllers, we have more clues than ever before about new ways of fighting the virus. HIV remains one of the most adaptable and elusive viruses that scientists have ever encountered, but through cases like the Esperanza patient, it seems possible that it might one day be completely curable.