The enigma of elite HIV controllers: The people with an innate ability to keep the virus at bay

There are a handful of people in the world who have put up a challenge for one of the world’s most deadly viruses: HIV. They are the exceptional elite controllers, individuals who keep their infection under control for decades naturally, without the help of pharmaceutical antiretrovirals. Theirs are rare cases, isolated in different spots around the world, but scientists are working to unravel the mysteries of this innate ability to hold the virus at bay and to translate their findings towards the global pandemic’s eradication. A scientific review published July 15 in Med magazine, from the publisher Cell Press, lays out scientific findings regarding these elite controllers and points towards potential areas of study in pursuit of a functional cure. HIV, which lead to AIDS, has already killed 40 million people since it first emerged in the 1980s and still accounts for 630,000 deaths a year around the world.

There’s no universal cure in sight for this global infection. Science’s biggest achievement thus far has been to prevent its spread and keep the virus on its heels with potent antiretroviral medications. But attempts to eliminate HIV, through vaccines or other medical intervention, have not yet borne fruit. Without antiretroviral treatment, when a person is infected, says Javier Martínez-Picado, author of the study and a Catalan Institution for Research and Advanced Studies (ICREA) investigator at IrsiCaixa, a Barcelona research center. “There is a pulse shared by the virus and the immune system for a while, but in the end the virus always wins,” he says. In the absence of anti-HIV drugs, this battle lasts for eight to 12 years — much less in the case of children — until AIDS appears, constituting the most advanced and serious phase of the infection, which can lead to death.

Only a few exceptions to this natural evolution of the HIV infection have been documented. They are referred to as the elite controllers. “These people are able to control virus replication without antiretroviral treatment. They have nearly undetectable viral loads,” says Martínez-Picado. This happens in the case of one out of every 300 patients, approximately, although in the majority of situations, the protection turns out to be temporary and, sooner or later, the person becomes susceptible to the virus. However, within this group, there is an even more extraordinary subgroup that maintains their resistance to HIV for decades. They are known as the exceptional elite controllers and are comprised of just a handful of patients around the world that the scientific community is examining closely, in search of answers that could lead to a solution to the global HIV pandemic.

Martínez-Picado’s team has uncovered nine such cases in scientific literature. The most resistant, a man who was documented in Australia in 2019, had been living with the virus for 37 years, controlling it naturally without the help of antiretroviral treatments. Another three people (reported in Spain in 2020) had been living with the virus between 20 and 30 years. The latest case, reported in Argentina in 2022, had been controlling their HIV without medication for eight years. The majority of the patients described are Caucasian (and women of childbearing age), a factor that is associated with greater accessibility to medical professionals and thus, greater availability of biological samples. The researchers have ruled out race as a determinant.

Where the virus lands in the cells is important, as is the infected person’s immune system’s response in the first moments after coming into contact with the HIV virus”

Javier Martínez-Picado, IrsiCaixa researcher

These individuals present certain singular biological characteristics that have to do with the moment in which they were infected, says Martínez-Picado: “Where the virus lands in the cells is important, as is the infected person’s immune system’s response in the first moments after coming into contact with the HIV virus.”

To pin down the significance of these particularities, the researcher offers an analogy of sowing and cultivating grain. In the same way that grain will grow better in fertile soil as compared to arid regions, “the virus can end up integrating itself in fertile DNA soil, where there is gene expression, or in gene deserts, where nothing moves and there is no chance of giving rise to a replication phenomenon.” Martínez-Picado is referring to the fact that the virus can end up penetrating very active areas of DNA, where proteins are manufactured, and using its genetic machinery to replicate; or it can land in genomic terrain and play a role that is yet to be discovered, but that does not produce proteins. “They probably have other functions, but since they don’t express proteins, they can’t express virus proteins either,” explains the scientist.

If the virus lands in one of these gene deserts, its ability to replicate will be low. This same process took place with endogenous retroviruses, viral fossils that arrived in our DNA thousands of years ago and are present in our bodies in a residual form, but that have no infectious potential, says Martínez-Picado.

Viruses incapable of replication

Continuing with the cultivation simile, the IrsiCaixa researcher says that some grains that are sown will prove to be impotent, with no ability to germinate. The same happens with HIV: “There are viruses that do not have complete DNA. They have a damaged viral genome and are not capable of replicating themselves.”

The scientific review also points to a key role played by the immune systems of elite controllers. Some patients, for example, have a mutation in their CCR5 gene, which plays a key role in the virus’ ability to penetrate cells. “Among many patients, one of their two alleles are mutated and have a slightly diminished capacity to favor infection,” Martínez-Picado says. This is precisely the same characteristic shared by the stem cell donors who were used for a bone marrow transplant in several patients living with HIV and hematological cancer who, after the operation, were free of both the tumor and virus.

The IrsiCaixa researcher adds that there are other genetic variants that are shared by elite controllers: “There are some that are related with the HLA (human leukocyte antigen system), which is a component of the immune system that determines cellular response against infections. We know that some kinds of HLA are related with better prognosis and others, with less favorable prognosis. Many of the elite controllers have the kind of HLA that is associated with a better prognosis.” Another important factor, he adds, is how similar the immune system of the person who transmits the virus is compared to that of the person who receives it: when they have more in common, there is a worse prognosis, as the virus has already learned to fight against that particular kind of immune system and, upon coming into contact with a similar system, “has already won the battle,” says Martínez-Picado.

The investigation also delves into the characteristics of viral reservoirs, which are anatomical sites that harbor viruses, and where they have a high potential to reawaken and replicate themselves when a person stops taking antiretroviral medications, for example. Among exceptional elite controllers, these reservoirs are much smaller than those of people who take antiretrovirals. “Among these people, we detect the virus because it is in their reservoirs, but when we sequence it, we see that it is defective: It is missing a piece of genome or has a mutation that make it unviable; or they are in non-fertile areas, in genetic deserts,” the scientist says.

Ezequiel Ruiz-Mateos, a member of the board of directors of the Spanish Society of Infectious Diseases and Clinical Microbiology’s AIDS study group (GESIDA), stresses that this patient profile illustrates that it is possible to control the virus. His team, located at the Institute of Biomedicine in Seville and at the Virgen del Rocio University Hospital, has also published a handful of cases of persistent controllers, and is working with a dozen more: “We think that these individuals could be cured. They have traces of the virus, but they cannot replicate. We have to look at how they have managed to get that special resorption and try to replicate that with therapeutic strategies,” he says.

Ultimately, behind every exceptional elite controller there may be a confluence of factors, says Martínez-Picado. And even the virus that infects them itself can be a microorganism with a low capacity to replicate or that has been losing its efficacy after several infections. Ruiz-Mateos warns that surely, there “are additional immune mechanisms in this population that have not been identified” and that would help to explain this protective phenomenon. “Perhaps we don’t have the immune system of these individuals well characterized. The virus in these people is frozen at a point very close to infection. And that means the immune response was very rapid.”

The women mystery

One detail that has researchers “extremely intrigued” is the elevated number of Caucasian women among the exceptional controllers. Ruiz-Mateos says that it is “a constant” among the cases that have been documented and adds that “this is an important clue when it comes to sex-linked immune factors that have gone unnoticed” and that should be studied. The hypothesis put forward by Martínez-Picado to explain the phenomenon is that women of childbearing age “are better equipped to deal with infections because their innate immune system is more effective in protecting the fetus,” but he calls for new cases to be studied and investigated in order to resolve remaining doubts around these unusual subjects.

The elite controllers study opens the door to new lines of research, such as those that focus on the genetic factors present in the cells that the virus infects. “We are trying to see what we can do to genetically evade the CCR5. If we managed to render it inoperable, that would mean that the virus could not enter, and you avoid viral replication,” says Martínez-Picado.

Another twist that the elite controllers review offers is encouragement for researchers to focus only on infected cells in fertile areas: “In 90% of cells that have the virus, it is not well or does not replicate. Our focus has to be on the other 10%,” the scientist says.

Scrutinizing immune response is the third line of study suggested by these exceptional cases. Martínez-Picado is committed to seeking techniques to strengthen the immune system, both cells and antibodies, against the virus. Although, the researcher admits, there are still unknowns to be resolved in this field, and in particular, in how it relates to the elite controllers. For example, “We do not understand, in acute infection, how immune mechanisms support each other to provide a response against the virus and isolate it in sterile areas of the DNA.”

Though many unknowns are on the table, the scientific review’s authors insist on the potential of these surprising cases. “Exceptional elite controllers provide evidence that the near-complete suppression of the replication of HIV is possible among humans and, as such, represent the best model for a functional cure for HIV,” says Martínez-Picado.

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