There are a handful of people in the world who have managed to defy one of the deadliest viruses: HIV. They are the exceptional elite controllers, individuals who have managed to keep the infection under control for decades naturally, without the help of antiretroviral drugs. These are unusual cases, very rare around the globe, but science is trying to unravel the mysteries behind this innate ability to keep the virus at bay and transfer these findings to global research to eradicate this pandemic. A scientific review published this Monday in the magazine Med, of the group Cell Press, The book breaks down the scientific evidence on these elite controllers and underpins lines of study towards a functional cure. HIV, which causes AIDS, has already killed 40 million people since it was first described in the 1980s and is still behind 630,000 deaths per year in the planet.
There is no universal cure in sight for this infection that is ravaging the world. The immense achievement of science has been to prevent its spread and keep the virus under siege with powerful antiretrovirals, but attempts to eliminate it, with vaccines or other medical interventions, have not yet borne fruit. Without antiretroviral treatment, when someone becomes infected, says Javier Martínez-Picado, author of the study and ICREA researcher at Irsicaixa, “there is a pulse between the virus and the immune system for a while, but in the end, the virus always wins.” In the absence of these drugs against HIV, this battle lasts about eight to 12 years —much less in the case of children— until AIDS appears, the most advanced and serious phase of the infection, which can lead to death.
There are only a few exceptions that circumvent this natural evolution of HIV infection: the elite controllers. “These people are prone to control the replication of the virus without antiretroviral treatment. There is almost no circulating virus in their blood,” says Martínez-Picado. This occurs in approximately one in every 300 patients, although in most cases, this innate protection ends up being temporary and, sooner or later, they become sensitive to the scourge of the virus. However, within this superior group, there is an even more extraordinary group, which maintains this resistance to HIV for decades: they are the exceptional elite controllers, just a handful of patients in the world who are closely watched by the scientific community in search of answers that can be translated into a global solution to the HIV pandemic.
Martínez-Picado’s team has collected nine cases described in the scientific literature. The most resistant, a man reported in Australia in 2019, had had the virus under control naturally for 37 years, without the help of antiretroviral treatments. Three others (reported in Spain in 2020) had been infected for between 20 and 30 years. The last case described, in January 2022 in Argentina, had had HIV under control for eight years without medication. Most of the patients described are Caucasian (and women of childbearing age), but this is associated with greater accessibility to study these profiles and greater availability of biological samples. The researchers rule out race as a determinant.
It is important where the virus landed in the cells and also how the infected person’s immune system reacted in those first moments of contact with HIV.”
Javier Martínez-Picado, Irsicaixa researcher
These people have some unique biological characteristics that have to do with the moment in which these patients were infected, explains Martínez-Picado: “It is important where the virus landed in the cells and also how the immune system of the infected person reacted in those first moments of contact with HIV.”
To clarify the significance of these particularities, the researcher makes an analogy with the sowing and cultivation of grain: in the same way that grain will be better cultivated in fertile soil than in arid areas, “the virus can end up integrating into fertile DNA soil, where there is gene expression, or in genetic deserts, where nothing moves and will not give rise to a replication phenomenon.” Martínez-Picado refers to the fact that the virus can end up penetrating very active areas of DNA, where proteins are manufactured, and use its genetic machinery to replicate; or it can land in genomic terrain with a role yet to be discovered, but inactivated to produce proteins. “They will surely have other functions, but as they do not express proteins, they cannot express the proteins of the virus either,” explains the scientist.
If the virus falls into one of these genetic deserts, its replication capacity is low. As happened with endogenous retroviruses, viral fossils that arrived in our DNA thousands of years ago and are there in the organism, in a residual form, but have no infectious potential, Martínez-Picado exemplifies.
Viruses unable to replicate
Continuing with the crop analogy, the Irsicaixa researcher recalls that some grains that are sown are bad and do not have the capacity to germinate. The same thing happens to HIV: “There are viruses that do not have complete DNA. They have a damaged viral genome and are not able to replicate.”
The scientific review also highlights the key role of the immune system of these elite controllers. Some patients, for example, have a mutation in the CCR5 gene, which is necessary for the virus to penetrate cells. “Many patients have a mutation in one of the two alleles and have a slightly reduced capacity to promote infection,” Martínez-Picado points out. This same characteristic was shared by the stem cell donors who were used to carry out a bone marrow transplant in several patients with HIV and haematological cancer who, after the intervention, were free of the tumour and the virus.
The Irsicaixa researcher adds that there are other genetic variants that characterise elite controllers: “There are some, related to the HLA, which is a part of the immune system that determines the cellular response against infections. We know that there are some types of HLA related to a better prognosis and others to a worse one. And many of the elite controllers have a type of HLA with a better prognosis.” It is also important, he adds, how similar the immune system is between the person who transmits the virus and the recipient: the more similar they are, the worse the prognosis, since the virus is already used to battling against that immune system and, when it comes into contact with another similar one, “it has already won the battle,” says Martínez-Picado.
Scientific research is also delving into the characteristics of viral reservoirs, which are silent deposits of viruses that are not eliminated and that have the potential to awaken and replicate as soon as antiretroviral therapy is stopped, for example. In exceptional elite controllers, these reservoirs are much smaller than in people who take antiretrovirals. “In these people we detect the virus because it is in the reservoirs, but when we sequence them, we see that they are defective: they are missing a piece of genome or have mutations that make them unviable; or they are in non-fertile areas, in those genetic deserts,” says the scientist.
Ezequiel Ruiz-Mateos, a member of the board of directors of the AIDS Study Group (Gesida) of the Spanish Society of Infectious Diseases and Clinical Microbiology, highlights that this patient profile illustrates that it is possible to control the virus. His team, 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 have this special reservoir and try to imitate that with therapeutic strategies,” he says.
In the end, behind an exceptional elite controller there is usually a confluence of factors, says Martínez-Picado. And even the virus that infected him may have been a microorganism with low replicative capacity or that has lost its effectiveness after successive infections. Ruiz-Mateos, for his part, warns that, surely, there are also “additional immune mechanisms in this population that have not been identified” and that would help explain this protective phenomenon: “Perhaps we have not well characterized the immune system of these extreme individuals. The virus of these people remains frozen at a point very close to the infection. And that means that the immune response was very fast.”
The intrigue of women
One detail that has researchers “very intrigued” is the high number of Caucasian women among the exceptional controllers. Ruiz-Mateos points out that this is “a constant” in the cases described and points out that “this is an important clue to immune factors associated with sex that have gone unnoticed” and that should be studied. The hypothesis that Martínez-Picado proposes to explain this 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 studying and researching new cases to resolve the doubts that these unusual subjects still raise.
The study of elite controllers opens the door to new lines of research, such as those focused on the genetic factors of the cells infected by the virus. “We are trying to see what we can do to genetically avoid CCR5. If we manage to make it unviable, we make it so that the virus cannot enter and we prevent viral replication.”
Another shift in scientific perspective that these elite controllers encourage is to focus only on infected cells in fertile ground: “In 90% of cells that have viruses, they are not well or do not replicate. Our focus has to be on the other 10%,” the scientist urges.
Examining the operation of the immune response is the third line of study that these exceptional cases offer. Martínez-Picado is committed to finding techniques that strengthen the immune system, both cells and antibodies, against the virus. Although the researcher admits that there are still unknowns to be resolved in this field, also among elite controllers. For example: “We do not understand, in acute infection, how the immune mechanisms support each other to offer a response against the virus and leave it alone in sterile areas of the DNA.”
With many unknowns still on the table, the authors of the scientific review insist on the potential of these unusual profiles: “Exceptional elite controllers provide evidence that almost complete suppression of HIV replication is possible in humans and, as such, represents the best model for a functional cure for HIV.”
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