- 'Elite controllers' are those who are infected with HIV but never develop symptoms and require no medication
- New study revels how elite controllers quarantine HIV in remote corners of the chromosome, rendering the it unable to replicate
- Findings represent a major step toward an effective vaccine and cure for HIV
Bruce Walker, MD
Elite controllers show us that not only is it possible to achieve a functional cure of HIV, where the virus is prevented from doing harm, but it may also be possible to eradicate the virus completely.
Director, Ragon Institute of MGH, MIT and Harvard
In medicine, studying rare patients can reveal clues that lead to new therapies that benefit broader groups of people afflicted with a disease. Infectious disease specialist Bruce Walker, MD, the founding director of the Ragon Institute of MGH, MIT and Harvard, has been fascinated by one such medical rarity for the last quarter century: People infected with HIV who never develop symptoms, despite not taking medication to manage the virus. These patients, known as “elite controllers,” represent about one in 200 people with HIV.
In a major breakthrough in the fight against HIV recently reported in the journal Nature, Walker and a team at the Ragon Institute led by immunologist Xu Yu, MD, along with investigators from several other research centers, have discovered a mechanism that may explain how these intriguing patients remain healthy. In fact, the researchers identified one elite controller who was once infected with HIV, but no longer appears to carry the virus, making her the first known case of a patient whose body spontaneously eradicated the disease. “Elite controllers show us that not only is it possible to achieve a functional cure of HIV, where the virus is prevented from doing harm, but it may also be possible to eradicate the virus completely, resulting in a sterilizing cure,” says Walker.
A momentous encounter
One day in 1995, a man named Bob Massie came to Walker’s office in the outpatient clinic at MGH. Massie had become infected with HIV 15 years earlier as a result of receiving contaminated blood transfusions for hemophilia, a blood-clotting disorder, but told Walker that he never developed symptoms or took medication for virus. Walker was skeptical, but tests confirmed Massie’s claim. “My jaw dropped,” recalls Walker, who soon learned that other doctors had identified similar patients, who became known as elite controllers. “These people were somehow keeping the virus in check, but how were they doing it?” asks Walker. “We’ve been chipping away at that question ever since.”
The secrets of the elite
Currently, most people with HIV are able to control the virus with antiretroviral drugs (ART), but the medications can cause side effects, ranging from fatigue and nausea to heart disease and liver damage. With support from philanthropists Mark and Lisa Schwartz, Walker and his colleagues have studied about 1500 elite controllers, making important contributions toward uncovering why they remain symptom free. The goal: Use that knowledge to find a cure for HIV and end patients’ reliance on ART.
For example, it’s well established that elite controllers keep HIV symptoms at bay by marshaling a potent response from immune proteins called T cells, which attack and destroy cells infected with the virus. Walker’s 2019 paper in the journal Science found an important clue to explain why. Using network theory, Walker’s team showed that elite controllers’ T cells are skilled at breaking down amino acids in HIV that are critically important to maintaining the virus’s structure, destroying it. Based on those findings, Walker is now overseeing development of a therapeutic vaccine that would “teach” the immune system of an HIV patient to fight off the virus.
Xu Yu, MD
We wanted to know: Where are viruses hiding in the human genome?
Group Leader, Ragon Institute of MGH, MIT and Harvard
At the suggestion of Nobel laureate David Baltimore, in 2000 Walker recruited Yu to join his lab. Yu, who is now a group leader at the Ragon Institute and has been studying elite controllers since she arrived, is the lead author of the Nature paper. In the study, Walker, Yu, and their colleagues used sophisticated new genetic sequencing technology to study the genomes in cells taken from 64 elite controllers. HIV integrates its genetic material into the human genome, creating a “viral reservoir,” which causes the infection to persist as cells replicate themselves. While older analytical tools could only measure the size of viral reservoirs, the cutting-edge sequencing tools used in this study could identify their location, too. “We wanted to know: Where are viruses hiding in the human genome?” says Yu.
The answer was stunning: The study revealed that elite controllers quarantine HIV viral reservoirs in remote corners of the chromosome known as “gene deserts,” where the virus’s genes can’t be turned on. “As a result, the reservoirs are ‘blocked and locked’,” says Yu, rendering the virus dormant. By contrast, the study found that this phenomenon was uncommon in HIV patients receiving ART. “This data suggest that a robust T cell immune response in elite controllers was able to eliminate HIV in parts of the genome where it can still be turned on,” notes Walker.
The study’s other surprise was the discovery that one elite controller, a California woman named Loreen Willenberg, had no evidence of HIV in any of the 1.5 billion cells the team analyzed. Prior to this study, two men with HIV were determined to have been cured, but only after undergoing grueling bone marrow transplants for cancer. “Loreen is number three,” says Walker. “However, she was cured without being subjected to a potentially lethal bone marrow transplant, through a completely different mechanism that is potentially translatable to other people.”
Learning from patients is at the core of all of the work that we do.
Walker, Yu, and their colleagues are currently recruiting HIV patients who have been treated long term with ART to determine if augmenting their T cell responses with a therapeutic vaccine can make their immune systems act like those of elite controllers. Walker believes this work might never have happened if he hadn’t met Bob Massie. “A lot of what we've done over the years has been built off of that encounter,” he says. “Learning from patients is at the core of all of the work that we do.”
Bruce Walker, MD, is the director of the Ragon Institute of MGH, MIT and Harvard, and a professor of Medicine at Harvard Medical School (HMS). Xu Yu, MD, is a physician investigator at MGH and an associate professor of Medicine at HMS.
About the Ragon Institute of MGH, MIT and Harvard
The Ragon Institute of MGH, MIT and Harvard was established in 2009 with a gift from the Phillip T. and Susan M. Ragon Foundation, creating a collaborative scientific mission among these institutions to harness the immune system to combat and cure human diseases. With a focus on HIV and infectious diseases, the Ragon Institute draws scientists, clinicians and engineers from diverse backgrounds and areas of expertise to study and understand the immune system with the goal of benefiting patients. For more information, visit www.ragoninstitute.org.
About the Massachusetts General Hospital
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $925 million and comprises more than 8,500 researchers working across more than 30 institutes, centers and departments. In August 2018 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America’s Best Hospitals."