The Riddle of the Elite HIV Controllers: People With an Innate Ability to Contain the Virus | Health & Wellness

There are a few people in the world who have managed to defy one of the most deadly viruses: HIV. These are exceptional elite controllers, people who have managed to keep the infection under control naturally for decades, without the help of antiretroviral drugs. These are unusual cases, very specific to the entire globe, but science is trying to unravel the mystery of this innate ability to contain the virus and translate these findings into global research to eradicate this pandemic. A scientific review is published this Monday in the journal Honey, groups cell press, destroys the scientific evidence about these elite controllers and supports lines of research aimed at functional cures. HIV, the cause of AIDS, has killed 40 million people since it was described in the 1980s and still causes 630,000 deaths a year on the planet.

There is no universal cure for this infection that is plaguing the world. A huge scientific breakthrough has been preventing its spread and containing the virus with powerful antiretroviral drugs, but attempts to eradicate it with vaccines or other medical interventions have so far been fruitless. Without antiretroviral treatment, when a person is infected, says Javier Martínez-Picado, the study’s author and an ICREA researcher in Irsicaixa, “there is a momentum of the virus and the immune system for a while, but in the end the virus always wins.” In the absence of these HIV drugs, the battle lasts about eight or 12 years – much less in the case of children – until AIDS, the most advanced and serious phase of the infection, which can lead to death, appears.

There are only a few exceptions that bypass the natural evolution of HIV infection: the elite controllers. “These people tend to control viral replication without antiretroviral treatment. They have almost no circulating virus in their blood,” says Martinez-Picado. This happens in about one in every 300 patients, although in most cases this innate protection is temporary, and sooner or later they become susceptible to the virus’s effects. But within this superior group is an even more unusual group that has maintained resistance to HIV for decades: the exceptional elite controllers, just a handful of patients in the world who are being looked at through a magnifying glass by the scientific community to find answers that could translate into a global solution to the HIV pandemic.

Martinez-Picado’s team collected nine cases described in the scientific literature. The most resilient person, reported in Australia in 2019, had kept the virus under control naturally for 37 years, without the help of antiretroviral treatment. Three more (reported in Spain in 2020) were in their 20s and 30s when they became infected. The most recent case reported was in Argentina in January 2022, where HIV was controlled without medication for eight years. Most of the patients described are Caucasian (and women of childbearing age), but this is due to the greater availability of these profiles and the greater availability of biological samples. The researchers rule out that race is a determining factor.

It is important where the virus entered the cells, as well as how the immune system of the infected person reacted in the first moments of contact with HIV.”

Javier Martinez-Picado, Irsikeisha researcher

These people have some unique biological characteristics that are linked to the moment of infection, explains Martinez-Picado: “It’s important where the virus entered the cells, as well as how the immune system of the infected person responded in those cells.” The first moments of contact with HIV.

To clarify the significance of these features, the researcher draws an analogy with sowing and growing grain: just as a grain will grow better in fertile soil than in arid areas, “the virus can end up integrating into fertile soil, DNA where there is gene expression, or into gene deserts where nothing moves and does not lead to the phenomenon of replication.” Martinez-Picado refers to the fact that the virus can end up in very active areas of DNA where proteins are produced and use its genetic machinery to replicate; or it can land in a genomic area whose role has yet to be discovered, but it will be inactivated for the production of proteins. “They will certainly have other functions, but since they do not express proteins, they cannot express the proteins of the virus,” the scientist explains.

If a virus ends up in one of these gene deserts, its ability to replicate is low. As happened with endogenous retroviruses, viral fossils that reached our DNA thousands of years ago and are present in the body in residual form, but have no infectious potential, – Martinez-Picado illustrates.

Viruses are not capable of replication

Continuing the comparison with cultivation, the researcher from Irsikaisha recalls that some planted seeds are bad and are unable to germinate. And the same thing happens with HIV: “There are viruses that do not have a complete DNA. “They have a damaged viral genome and are unable to replicate.”

The scientific review also points to the key role of the immune system of these elite drivers. Some patients, for example, have a mutation in the CCR5 gene, which is essential for the virus to enter cells. “In many patients, one of the two alleles is mutated, and they have a slightly reduced ability to promote infection,” Martinez-Picado emphasizes. This is precisely the characteristic of stem cell donors who were used for bone marrow transplants in several patients with HIV and hematological cancer, who were free of tumor and virus after the intervention.

The Irsicaixa researcher adds that there are other genetic variants that characterize elite controllers: “There are some linked to HLA, which is part of the immune system that determines the cellular response to infections. We know that there are some HLA types that are associated with a better prognosis and others with a worse one. And many of the elite controllers have the best prognostic HLA type.” It is also important, he adds, how similar the immune system is between the person transmitting the virus and the recipient: the more similar the immune system, the worse the prognosis, since the virus has already become accustomed to fighting this immune system and, when it comes into contact with another, “it has already won the battle,” says Martinez-Picado.

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 reactivate and replicate, for example, once antiretroviral therapy is stopped. In exceptional elite controllers, these reservoirs are much smaller than in people taking antiretroviral drugs. “In these people, we detect the virus because it is in reservoirs, but when we sequence them, we see that they are defective: they are missing part of the genome, or they have mutations that make them unviable; or they are in infertile areas, these genetic deserts,” the scientist says.

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, emphasizes that this patient profile shows that the virus can be controlled. His team at the Institute of Biomedicine in Seville and the Virgen del Rocío University Hospital has also published several cases of persistent controllers and is working with a dozen more: “We think these people are curable. They have traces of the virus, but they cannot reproduce. You have to look at how they managed to create this special reservoir and try to mimic it with therapeutic strategies,” he says.

After all, there is usually a combination of factors behind the exceptional elite controller, says Martinez-Picado. And even the virus that infects him could be a microorganism with a low capacity for replication or lose its effectiveness after successive infections. Ruiz-Mateos, for his part, warns that there are certainly “additional immune mechanisms in this population that have not been identified” that could help explain this protective phenomenon: “We may not have the immune system of these people.” “The virus in these people freezes at a point very close to infection. And that means the immune response was very rapid.”

Intrigue of women

A detail that keeps the researchers “extremely intrigued” is the large number of Caucasian women among the exceptional controls. Ruiz-Mateos notes that this is a “constant” in the cases described, and points out that “this is an important clue to the immune factors associated with sex that have gone unnoticed” and should be studied. The hypothesis that Martinez-Picado puts forward to explain this phenomenon is that women of childbearing age “are better prepared to fight infections because their innate immune system is more effective in protecting the fetus,” but she calls for more cases to be studied to resolve the doubts that these unusual topics still raise.

Studying elite controllers opens the door to new lines of research, such as those that focus on the genetic factors of the cells the virus infects. “We’re trying to figure out what we can do to genetically prevent CCR5. If we can make it inviable, you prevent the virus from getting in and you prevent it from replicating.”

Another twist in scientific perspective that these elite controllers propose is to focus only on the infected cells in the fertile soil: “In 90% of the cells that contain viruses, they are not good or do not reproduce. Our focus should be on the remaining 10%,” the scientist urges.

A closer look at the immune response is the third line of research that these exceptional cases provide. Martinez-Picado aims to find methods that strengthen the immune system, both cells and antibodies, against the virus. Although the researcher admits that there are still unanswered questions in this area, including among elite controllers. For example: “We do not understand how, in acute infection, the immune mechanisms support each other, offering a response against the virus and leaving it alone in sterile areas of DNA.”

While many unknowns still remain, the authors of the scientific review insist on the potential of these unusual profiles: “Exceptional elite controllers provide evidence that near-complete suppression of HIV replication is possible in humans and, as such, represent the best model for a functional cure for HIV.”

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