Some people diagnosed with HIV are able to eradicate the virus without antiretroviral drugs or even stem cell transplants, having the ability to naturally suppress the virus and achieve a medically verifiable cure.
Researchers call this small population elite controllers, a term that reflects their unique ability to keep one of the most notorious viruses at bay.
Two of these patients have gained fame in the scientific literature in recent months, each known by a code name: the San Francisco patient and another called the Esperanza patient. Both are women who have been put in focus in medical journals and at scientific conferences for having eradicated HIV from their bodies.
In addition to these two famous examples, new research from the Ragon Institute in Boston has focused on a larger group of elite controllers – a total of 58 – who have also been able to keep the virus at bay by virtue of their distinct biological abilities. The elite controllers were compared with 42 HIV patients on antiretroviral therapy, individuals representing the vast majority of those globally diagnosed with HIV.
Entering Science translational medicine, immunologists at the institute report that they have uncovered a deep well of new clues that point to the extraordinary ability of elite controllers to eradicate the virus. One reason is a strong immune response, but another is centered on how latent viral genetic sequences are stranded in the human genome. These sequences tend to be stored in chromosomes in remote areas where they are less likely to replicate but more likely to be found by immune forces.
Research opens a new window to understanding what it means to be infected with HIV, a virus estimated to affect 38 million people globally. Millions worldwide have died since the HIV pandemic began 40 years ago.
Most patients take antiretroviral drugs for life to keep the virus at bay, but elite controllers can easily suppress HIV for long periods without the need for medication. Although the San Francisco patient became infected in 1992, she has kept the virus at bay for decades. Her existence – and that of other elite controllers – defies the long-standing dogma that HIV infection is inevitably for life.
The new findings join a growing group of work that could ultimately lay the groundwork for future pharmaceutical interventions to help the vast majority of HIV patients eliminate the virus based on principles learned by scientists from elite controllers, people who have obtained so-called “sterilizing cures”. . “
“Stagnant evidence suggests that sustained drug-free control of HIV-1 replication is enabled by effective cellular immune responses,” wrote the lead author, Dr. Xiaodong Lian with his colleagues.
Lian and other members of the team explored what they call the subtle “footprint” of the immune system, revealing how elite controllers are able to eliminate HIV infection without medication. Data from their experimental work suggest that viable human immunodeficiency viruses in elite controllers may be exposed to greater pressure from the cells of the immune system. As a result, viruses are unable to dodge the formidable army of the immune system.
The Boston-based team knew when entering the research that the immune system is a veritable arsenal capable of powerful antiviral activity. However, for most people infected with HIV, the immune response is severely crippled, which is why antiretroviral drugs are crucial for survival. The drugs work by preventing the virus from replicating.
“We followed closely [the] effects of antiviral immune responses on intact and defective proviral sequences from elite controllers, “Lian argued in the report, referring to the viral state in which HIV inserts its genetic material into the DNA of a host cell.
The word “proviral” is not only the key to understanding what Lian and colleagues studied, but is also crucial to understanding persistent HIV infection in the vast majority of people who get the virus and are addicted to antiretroviral drugs. A provirus is a genetic sequence that has integrated itself into the host’s DNA. This stealth action allows the virus to remain latent – and hide in the body.
Instead of replicating as a free-circulating virus, HIV replicates insidiously when the host cell replicates, which means that when the cell is at rest and does not replicate, neither is HIV. And because the proviral sequence has insinuated itself in the host’s DNA, the immune system is not alerted to the presence of HIV during this provirus latency period.
In fact, when HIV is integrated into the host’s genetic machinery by placing copies of its genome in the host’s DNA, it creates what is known as a viral reservoir.
The Lian and Ragon Institute team found that for elite controllers, HIV infection works differently, a conclusion they drew by studying both intact and defective proviruses because both were present in the elite controllers’ chromosomes.
They also found that the controls’ proviruses had fewer mutations than those in humans requiring antiretroviral therapy. Mutations often develop to help the virus escape T-cell recognition. Another finding reported by the Ragon team revealed that proviruses in elite controllers were more likely to be sequestered in chromosomal regions, where they are not easily replicated but can be easily detected by immune system patrols.
Findings like these have helped immunologists – those at the Ragon Institute as well as others around the world – highlight differences between elite controllers and people in need of lifelong antiretroviral therapy.
“Recent studies have begun to reveal pronounced differences between persistent viral reservoirs in elite controllers and most antiretroviral-treated individuals,” Lian wrote.
All the new results help to dispel some of the mystery that underlies the phenomenon of elite control. The Ragon Institute reported in the journal Nature last year that the San Francisco patient, an elite controller, had no intact proviral sequences in her genome. She is completely HIV-free. Based on Ragon Institute research, this suggests that the San Francisco patient’s immune system may have completely eliminated the woman’s HIV reservoir. Researchers refer to this rare event as a “sterilizing cure.”
Two other patients, the late Timothy Brown from California, commonly known as the Berlin patient, and Adam Castillejo from the United Kingdom, who has been christened the London patient, were both declared cured of HIV. However, both men had undergone stem cell transplants for cancer, which resulted in their immune system eliminating viruses. Brown died in 2020 after cancer of the blood aggressively returned. Neither the San Francisco patient nor the Esperanza patient has undergone a stem cell procedure, also known as a bone marrow transplant, which provides patients with a new blood supply.
Like the San Francisco patient, the Esperanza patient, an elite controller from Argentina, had no intact HIV supplies, as scientists studied an astonishing 1.19 billion blood cells and 500 million tissue-related cells. A report on her case was published last month by Ragon Institute researchers in Annals of Internal Medicine.
All the results suggest that there may ultimately be a “workable path to a sterilizing cure” for patients who are unable to do this on their own, said the institute’s researchers, who summarize their research on the Esperanza patient. More work, these experts say, lies ahead.
“There is a broad consensus that elite, drug-free control of HIV-1 replication – in most cases – is mediated by the host’s immune factors. However, elite control cannot occur simply because of the presence of potent antiviral immune responses to suppress ongoing viral replication, “concluded Lian and colleagues.
“We performed simultaneous assessments of individual proviral sequences and their corresponding chromosomal locations to generate a comprehensive analysis of the proviral reservoir landscape of intact and defective proviruses from elite controllers. These studies showed an atypical reservoir profile of intact proviruses in elite controllers.”
Researchers identify the other HIV patient whose body appears to have become free of the virus
Xiaodong Lian, et al., Signatures of immune selection in intact and defective proviruses differentiate HIV-1 elite controllers, Science Translational Medicine (2021) DOI: 10.1126 / scitranslmed.abl4097
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