A woman in Barcelona maintained an undetectable HIV viral load for more than 15 years after stopping antiretroviral therapy, according to a case report presented at the 24th International AIDS Conference (AIDS 2022) in Montreal. Her HIV has not been completely eradicated, so she cannot be considered cured in the strictest sense, but she appears to be in prolonged remission without antiretrovirals, sometimes referred to as “functional recovery”.
Although this woman is an exceptional post-treatment monitor and her experimental regimen is not suitable for widespread use by people living with HIV worldwide, her case may provide clues to help researchers develop more strategies. widely applicable for long-term HIV remission.
“The case presented is exceptional, not only because there are so few people with long-term follow-up control, but also because of the control mechanism of HIV, which is different from that described in control people. elite and other cases documented to date,” explained study co-investigator Dr. Josep Mallolas, of Hospital Clinic-IDIBAPS, University of Barcelona.
The viral reservoir and the immune response
Although antiretroviral therapy (ART) can keep HIV replication suppressed while treatment continues, the virus embeds its genetic fingerprint (called provirus) into the DNA of human cells, establishing a viral reservoir inaccessible to antiretrovirals and usually invisible to the immune system. These proviruses can remain dormant in resting immune cells indefinitely, but can start producing new viruses when ART is stopped.
People considered truly cured of HIV have received stem cell transplants to treat cancer from donors who carry a rare mutation, known as CCR5-delta-32, which prevents HIV from entering immune cells. But a larger group – albeit still only a small fraction of people living with HIV – is able to control the virus, from the onset of infection or after stopping treatment.
The new case, presented by Dr. Núria Climent of the Hospital Clinic-IDIBAPS, concerns a woman – nicknamed the Barcelona patient – who, at 59, was diagnosed with HIV during an acute infection. People infected very early have a smaller viral reservoir, which improves their prospects for functional cure. Initially, her viral load was around 70,000 and she still had a high CD4 cell count (around 800).
The woman participated in a small clinical trial testing various immunomodulatory therapies. She was first given standard antiretroviral therapy of lopinavir/ritonavir, tenofovir disoproxil fumarate and lamivudine for nine months plus a short course of cyclosporine A, an immunosuppressive drug.
At this point, she had a brief planned break from treatment, during which she received granulocyte-macrophage colony-stimulating factor (an agent that promotes the production of white blood cells) and interferon alpha (a cytokine that regulates innate, or nonspecific, immune activity). . She then resumed treatment and a short course of interleukin-2 (a cytokine that activates T lymphocytes and natural killer cells).
Eight weeks later, with a suppressed viral load, she had another interruption of analytical treatment, but her HIV did not recover as expected after stopping antiretrovirals. Not only did her plasma HIV RNA viral load remain undetectable, but she also experienced a “pronounced and progressive” reduction in viral reservoir, as indicated by a 98% drop in total HIV DNA and a decrease in 94% of proviral DNA integrated into CD4. cells, says Climent. However, using a viral growth test, the researchers were able to isolate a small amount of virus capable of replicating.
Hoping to shed some light on the woman’s unusual response, the researchers performed genetic analysis, concluding that “she lacked classic genetic factors” associated with natural viral control. And indeed, their T cells were found to be sensitive to HIV entry in a lab analysis. She also had a severe acute phase infection, which is not typical for elite controllers.
The woman did not have the defective virus, which has been found in some people who naturally control HIV. The researchers were able to isolate their virus and grow it in the lab, showing that it could replicate normally.
By taking a closer look at women’s immune responses, researchers found that natural killer (NK) cells and CD8 killer T cells play a key role in controlling HIV. Culture of CD4 T cells with NK cells and CD8 T cells resulted in 93% inhibition of viral replication.
In addition, the woman had higher levels of specific types of NK cells (NKG2C+ memory type NK cells) and killer T cells (gamma-delta CD8 T cells) than those usually seen in untreated individuals with typical progression. of HIV. “These cell types have been shown to have potent cytotoxic activity against HIV-infected CD4 T cells,” Climent said.
Although Climent did not present detailed results to the 19 other people present at the trial, she told reporters at an AIDS 2022 press conference that the woman “was the only one capable of controlling [HIV] It should be noted that this outstanding controller would have been the only female in the study, and other research suggests that women may have an advantage over men when it comes to controlling HIV without ART. .
The question now is whether researchers can use the insights gained from this case and other exceptional monitors to develop treatment strategies that could enable millions of typical people with progressive HIV to keep their virus under control. long-term without ongoing antiretroviral therapy.
Discussing the case with other HIV treatment advocates, aidsmap writer Gus Cairns noted that these cases of long-term remission receive less attention than the rare cures after a stem cell transplant, a risky procedure that is only suitable for HIV-positive people living with HIV. a threatening cancer. Some of the cases come from natural controllers, like the patient from Buenos Aires described last year, while others manage to control HIV after ART and various immune therapies.
“Currently they seem to have little in common and are generally apart of their cohort,” Cairns wrote. “But there must be something in common that they share, and the Barcelona patient points to some possibilities. I would like to see more global funding, advocacy and media attention for trackers so that we can figure out how to make what happened to them reproducible on a large scale.