Can the immune system eliminate HIV in some infected people without the need for treatment? One study suggests so, with ramifications for future treatment.
Just before World Aids Day on 1 December, a group of scientists published research that showed a second person had appeared to rid themselves of HIV without drugs or treatment. Known as the “Esperanza Patient”, the Argentina-based person had no intact HIV viral sequence in their genome, despite having previously been infected – just like the “San Francisco Patient” who demonstrated the same elimination of HIV cells in 2020.
Both people are known as “elite controllers”; their immune systems contain the killer T cells that can suppress HIV without the need for medication. Ordinarily, those infected have “viral reservoirs” that are created when HIV places copies of its genome into the DNA of cells. The virus is able to hide from anti-HIV drugs and the body’s immune response, and new viral particles are constantly made from the reservoir. This is treated with anti-retroviral therapy (ART), which prevents new viruses being made, but cannot eliminate the reservoir.
A sterilising cure?
However, elite controllers appear to not need ART despite having viral reservoirs that can produce more of the virus, suggesting all proviruses in the body capable of replicating have been eliminated completely – known as a “sterilising cure”.
“HIV infection is considered an incurable disease,” says Dr Xu Yu, co-author of both studies and principal investigator at the Ragon Institute in Massachusetts. “Currently available drugs against HIV only suppress the disease, they don’t eliminate it – for that reason they have to be taken life-long.”
“It’s been shown that in two patients, a highly toxic bone marrow transplant can lead to a cure of HIV, however, this was done in HIV patients who had leukaemia, and certainly cannot be performed on a larger scale. Our work now demonstrates that a cure of HIV is now also possible naturally – in the absence of any specific treatment,” she adds.
Immune mechanisms
Yu leads a lab at the Ragon Institute, which is part of the Massachusetts General Hospital, MIT and Harvard, which studies HIV viruses in diverse groups of participants to investigate possible ways the immune system can recognise and combat HIV.
“During my medical training in China, I became aware of HIV infection as a rising problem for which almost no real treatment was available at that time,” she says. “I also felt that HIV infection is in many situations associated with stigmatisation and social neglect. I have been working on immune mechanisms against HIV for over 20 years now, and we have been trying to understand what specific immune responses can contribute to controlling HIV.”
Yu started her career working on T cell immune responses and later found that much of what the T cells can do depends on innate immune factors and immunogenetic characteristics. “Most recently, we have been studying HIV from a virological perspective, showing that in people who naturally control the disease, HIV tends to be integrated in the non-coding region of the human genome,”she adds. “We now see that so many layers of immune mechanisms contribute to antiviral immune defence.”
A rare, but possible, outcome
In the latest study – “A possible sterilising cure of HIV-1 infection without stem cell transplantation” – the research team used individual proviral sequencing and viral outgrowth assays to analyse 1.188 billion blood cells and 500 million cells from the placenta of the Esperanza Patient who was HIV-1-infected but had never developed any clinical symptoms of infection in eight years. No genome-intact HIV-1 proviruses were detected. Seven defective proviruses were identified, some of them derived from clonally expanded cells.
“While we clearly documented that she had been infected in the past – because we detected small segments of HIV integrated in the patient’s genome – we failed to detect intact replication-competent, or viable HIV, in this patient,” Yu says. However, it’s made clear in the study that, “the absence of evidence for intact HIV-1 proviruses in large numbers of cells is not evidence of absence of intact HIV-1 proviruses”.
“A sterilising cure of HIV-1 can never be empirically proved,” it reads, but does conclude: “These observations raise the possibility that a sterilising cure may be an extremely rare but possible outcome of the HIV-1 infection.”
Xu Yu
- Core member, the Ragon Institute of Massachusetts General Hospital, MIT and Harvard
- Associate Professor of Medicine, Harvard Medical School
- Physician Investigator, Massachusetts General Hospital
- Received an MD from China Medical University in Shenyang, China
- Completed postdoctoral training in the AIDS Research Center at MGH.
“Educating” immune systems
Yu says the study appears to have found the “elusive sterilising cure” that the human immune system is able to completely eliminate HIV itself. “This means that HIV is in rare cases a disease that heals spontaneously.”
The findings may suggest a specific killer T cell response common to both the San Francisco and Esperanza patients, with the possibility that other people with HIV have also achieved a sterilising cure. If the immune mechanisms underlying this response can be understood by researchers, they may be able to develop treatments that teach others’ immune systems to mimic these responses in cases of HIV infection.
“We believe there may be more patients out there who have also developed a natural cure of HIV infection and we are trying to identify them and study them in more detail. This may ultimately help to figure out what exact mechanism is underlying such a remarkable disease outcome,” Yu adds.
The team is now looking towards the possibility of inducing this kind of immunity in persons received ART through vaccination, with the goal of “educating” their immune systems to be able to control the virus without ART.
“These findings, especially with the identification of a second case, indicate there may be an actionable path to a sterilising cure for people who are not able to do this on their own,” Yu says, adding that she is extremely grateful to all the study participants she works with. “They make, in my opinion, the most important contributions to science.”
Image credit | Alamy