Paul Boakye was 22 when he was diagnosed with HIV. It was winter 1986, five years after the world first became aware of the deadly disease that would become known as acquired immune deficiency syndrome (AIDS). After receiving the news, Boakye was certain he was going to die young. “I distinctly remember a doctor telling me that I probably wouldn’t live to see 30,” he said.

Years passed, and Boakye watched as both his former partner and many of his friends died of complications from HIV, which infiltrates immune cells and weakens the body’s defenses. During the early days of the HIV pandemic, a diagnosis was essentially a death sentence. Without getting treatment, HIV infections can eventually develop into AIDS — the stage in which a person’s immune system has deteriorated to the point that they become vulnerable to typically harmless infections and rare cancers. Once AIDS manifests, life expectancy drops to just a few years.

But Boakye was an exception.

Now four decades after his diagnosis, at age 63, he remains symptom-free. He is one of the rare people with HIV whose immune systems can fight off the virus without treatment. These individuals, known as “elite controllers,” make up less than 0.5 percent of those who get infected with HIV.

For many scientists, this group of people provides a roadmap for a so-called functional cure, a state akin to cancer remission, where the infection is under control, but not completely eliminated.

A cure for HIV is still much needed. In 2025, approximately 1.2 million people around the globe became newly infected and around 570,000 died from HIV-related causes. Today’s clinicians now have an arsenal of effective medications to both prevent and treat HIV infections. “There are a lot of tools to fight HIV, but it’s also evident that this is not enough,” said Asier Saez-Cirion, leader of the Viral Reservoirs and Immune Control Unit at the Pasteur Institute in Paris.

To keep HIV as a survivable disease, people with the virus must take treatments for life, which brings up widespread issues of cost and access. When those become a barrier, it ends up costing lives. But researchers have been working on deciphering the lasting secrets of elite controllers like Boakye, in hopes of one day developing a functional cure for millions more people living with HIV. This work has led to many new strategies for fighting the virus — and several new treatments are now being evaluated in clinical trials.

The elite controllers of HIV

Joel Blankson, an associate professor of medicine specializing in infectious diseases at the Johns Hopkins University School of Medicine, remembers when he encountered an HIV elite controller for the first time. It was 1998, and a woman had come to the clinic after testing positive for HIV. That test result showed that her immune system had encountered the virus and produced antibodies to fight it.

But further tests revealed something baffling. Normally, as an HIV infection progresses, the virus infiltrates key immune cells, known as CD4 T cells, hijacking their internal machinery to make more copies of itself, and killing the host cells in the process. This patient, however, had no detectable levels of virus in her blood and appeared to have a healthy number of CD4 T cells. “That was fascinating,” Blankson said, since clinicians at the time did not think that could be possible.

Starting in the 1990s, researchers in the US and elsewhere in the world started documenting such cases. A few years earlier, Bruce Walker, a physician-scientist and director of the Ragon Institute of Mass General Brigham, MIT, and Harvard, had been similarly astounded by a patient who had been HIV positive for 16 years with no signs of disease. “I thought initially he couldn’t possibly be infected because everybody we saw had progressive illness,” Walker said.

For any virus, whether it’s HIV or influenza or Covid-19, people have a range of responses — some people become severely ill while others may have no symptoms at all. But HIV is exceptionally good at evading the immune system’s defenses, so the research community was glad to see that there were some people who seemed to be able to naturally fight off HIV. “It was particularly exciting to see that they were able to maintain this control in the long term,” Saez-Cirion said.

So the natural question was: What made these people different from those who became severely ill from HIV?

Some researchers hypothesized that these elite controllers had been infected by a defective version of HIV. Early evidence appeared to support this claim: In 1992, researchers described a small group of long-term, symptom-free HIV-positive individuals who had all been inadvertently infected through blood transfusions from an asymptomatic individual. The transfusions had occurred in 1985, before blood was routinely screened for HIV. Both the donor and the recipients harbored a strain of the virus with genetic mutations that hindered its ability to replicate.

But this incident turned out to be the exception. Later studies found that most people who survived for many years without disease progression did not carry weakened versions of HIV. For example, when Blankson and his colleagues isolated HIV from elite controllers’ cells, they found that the virus was able to multiply effectively in a lab dish just as well as the virus from people who became ill from HIV. And when they used the virus from these elite controllers to infect mice engineered to have human-like immune systems, the pathogen was still able to spread through the animals with ease. All of this suggested there was something unique not about the infecting strain of the virus but instead about these individuals’ immune systems.

As the tests for detecting the virus in blood samples improved, researchers found that there were even different levels of how much some people could control the virus. There were, for example, “viremic controllers,” who are often defined as those with less than 2,000 copies of HIV within a milliliter of blood, and “elite controllers” who have less than 50. For comparison, a typical HIV-positive person can have anywhere from tens of thousands to more than 1 million HIV particles in a milliliter of blood, depending on the stage of their infection.

More recently, another group of intriguing patients has emerged: post-treatment controllers, who, after taking antiretroviral treatment for many years, become capable of controlling HIV without medication.^.This group is giving even more hope that controllers may hold a clue to finally creating a lasting cure for the disease.

Unraveling the mechanisms of elite control

Once people who seemed to be beating back HIV on their own began to emerge, researchers went searching for more of them. Eventually, several research teams were able to assemble large cohorts of these patients: Walker and his colleagues, for instance, found around 1,000 elite controllers to begin to study them en masse to search for trends.

Some of the earliest studies looked into elite controllers’ genetics. Using a technique known as genome-wide association, which involves screening the genetic material of many people for links to disease, scientists discovered that a large proportion of elite controllers possessed variants of genes that code for structures responsible for presenting antigens — the fragments of viruses and other substances that immune cells use to detect pathogens.

This led scientists to zero in on cytotoxic T cells, immune cells that zero in on these fragments to identify foreign and infected cells to attack. In elite controllers, these cellular soldiers appeared to be exceptionally good at seeking out and eliminating HIV. How these individuals’ immune responses accomplish this has been a matter of intense investigation: Some researchers, such as Mark Connors, an HIV researcher at the US National Institute of Allergy and Infectious Diseases, and his team have found that elite controllers’ cytotoxic T cells increase the production of a specific molecule that pokes holes in infected immune cells to kill them — something that the same type of cells in other HIV-positive people are unable to do. Other groups, such as Walker’s team, have found that cytotoxic T cells are able to launch highly specific attacks on vulnerable regions within the virus’s structure.

Over the years, scientists have found that there is likely no one-size-fits-all explanation for why elite controllers’ immune systems are such formidable opponents for HIV. Studies have also found that these individuals also appear to possess exceptionally robust natural killer cells, which are immune foot soldiers that are some of the first to find and kill invading pathogens.

Other investigations have looked beyond specific cells to the aftermath of an elite controllers’ immune response. Xu Yu, an HIV researcher at the Ragon Institute, along with Walker and their colleagues, have found that immune systems of some elite controllers keep HIV locked away in so-called gene deserts, where it is unable to make more copies of itself — an essential task for the virus’ success.

Yu says that this is likely the result of unusually strong immune surveillance. Elite controllers’ immune systems were likely able to kill off the cells in which the virus had integrated itself into parts of the genome to multiply. This left only those cells with ineffective viruses behind. How the immune system actually does this remains a mystery, but according to Yu, it’s likely that multiple parts of controllers’ immune systems work together to launch particularly powerful responses.

In addition to uncovering how, exactly, the immune system accomplishes this feat, Yu is also hoping to replicate this process in people who aren’t elite controllers. The good news is, evidence so far suggests that this may indeed be possible: In a 2023 study with eight people who had been on long-term anti-retroviral therapy, Yu’s team found that it was also possible for non-elite controllers to lock HIV away in these gene deserts — but only after more than two decades of treatment.

The next step is to determine how to make people reach this state faster, so that they can one day stop needing treatment altogether, Yu says.

Researchers have drawn inspiration from these studies to develop new strategies for fighting HIV. Several are currently being tested in people with the virus. Walker’s team, for example, has developed a trial vaccine designed to train a person’s T cells to attack the most vulnerable parts the viruses’ structure — both as a way of preventing and of treating infection, in an early-stage trial. Saez-Cirion and his team have several ongoing trials, including one effort that involves administering immunotherapy in combination with antiretrovirals in people with newly diagnosed infection to try to coax their immune systems into developing the potent immune response found in elite controllers.

The elite road to a cure?

Experts are generally reluctant to say that elite controllers — even those who have lived symptom-free for decades — are “cured” of HIV. The main reason is that HIV is notorious for hiding in so-called reservoirs, cells in which HIV lingers without replicating.

The virus in these reservoirs escapes detection from a person’s immune system and from current HIV medicines. From here, it can then become active after remaining quiet for years. Because HIV infects immune cells, which travel all around the body, the virus can hide in deep tissues, such as the brain, that are extremely difficult to probe in living people.

And there are documented cases of the virus eventually breaking through an elite or viremic controller’s immune defenses, kick-starting disease progression — even if they have lived symptom-free for years or decades. It’s still unclear what factors determine when that point will come. So, many controllers are also on antiretroviral therapy.

There are, however, two elite controllers who are widely considered to be cured. One is the “Esperanza patient,” named after the Argentinian city where she lived, for whom researchers analyzed more than a billion cells and found no intact HIV. And the other, Loreen Willenburg, a Californian woman, kept the virus at bay for more than three decades without treatment — even while receiving immune-suppressing treatment for lung and brain cancer. Before she died in April, Willenburg donated her body to science; Yu and her colleagues have been carefully analyzing autopsy samples to determine whether there are intact viruses hidden somewhere within her body.

But these are the incredibly rare known examples among the 92 million people who have acquired HIV since the virus was first described. So even the elite controllers must stay vigilant for the virus’s reemergence. Boakye regularly gets his blood screened to make sure that HIV has not begun to spread. Today, he lives in the UK working as a playwright, and he remains active and healthy — and HIV remains undetectable in routine tests, even after four decades without treatment.

For years, he has tried to enroll in a study in hopes of helping scientists understand how his immune system has managed to fight HIV all these years, and last year, he became involved in three research projects. One of these is at the Ragon Institute, where Yu’s team analyzed more than 1 million cells in Boakye’s blood and found only a tiny number of HIV fragments — and only one that appears to be intact. Whether this fragment is capable of replicating remains unknown.

“They believe that my immune system is ignoring all the defective fragments and just controlling the one fragment that could replicate,” Boakye said. How his immune system does this is still a mystery, but Boakye hopes that by studying him and other elite controllers, scientists will be able to reverse engineer new treatments.

While a cure for HIV remains elusive, this research is bringing us closer than ever to that goal. There are multiple trials trying to mimic the responses found in elite controllers around the world, and the results of these efforts will emerge over the next five years or so, which is quite an exciting prospect, Saez-Cirion said. “We need additional tools that will allow people to live with HIV but without antiretrovirals. And if we can cure it — even better,” Saez-Cirion said.