For millions of people living with HIV, daily medication is a lifelong necessity. When people stop taking drugs, commonly called antiretroviral therapy, the virus usually returns quickly within a few weeks.
But it doesn’t apply to everyone. Scientists are puzzled by rare people who continue to suppress the virus for months or even years after stopping drug therapy.
Surprisingly, a small number of people recover much more slowly, taking months or even longer to recover. ”
Nadia Lone, Ph.D., Senior Research Fellow, Gladstone Institute
In a study published in a journal immunityRoan and her team are beginning to uncover why, and in doing so, uncover a potential new path to long-term health for people living with HIV without the need for antiretroviral therapy.
Among their key discoveries, the researchers discovered two specific genes in infected cells that act like security locks to keep the virus dormant. And perhaps most importantly, they also discovered that the common diabetes drug metformin can activate one of these locks, keeping the virus dormant.
“Our data suggest that metformin may be able to slow or even prevent HIV rebound in some people. This is interesting because metformin is a very safe and affordable drug,” said Roan, the study’s senior author. “We are now very interested in pursuing preclinical and ultimately clinical studies to directly test these potential benefits.”
Efforts towards functional healing
For people with HIV, antiretroviral therapy is successful in controlling the virus, but a “reservoir” of immune cells that contains permanent copies of HIV’s genetic code persists. When treatment is discontinued, this genetic code usually begins to produce active HIV, causing symptoms to return and, if left untreated, to acquired immunodeficiency syndrome (AIDS).
By studying the rare people who continue to suppress the virus even after treatment ends, Rohn and her team sought to pinpoint the characteristics of immune cells that can keep the virus contained.
They looked at four recently completed clinical trials in which people with HIV intentionally stopped treatment (in some cases to test the possibility of an HIV cure) and were closely monitored for HIV rebound, at which point antiretroviral therapy was restarted.
Roan’s group obtained blood samples taken from 75 trial participants just before they stopped treatment and measured the levels of genes and proteins in multiple types of immune cells, linking these characteristics to the time it took to recover from HIV.
These efforts have led to several important discoveries. In two of the trials, the delayed rebound was associated with increased levels of a particular type of immune cell known as stem cell memory CD8+ T cells. In fact, the two patients with the slowest rebound (one over 22 weeks and the other over 33 weeks) also had the highest levels of these cells.
“These CD8+ T cells appear to have ‘stem-like’ characteristics and may be able to persist for long periods of time and continue to self-replenish, which may contribute to long-term ART-free HIV control,” Roan says.
In another trial, people with atypical types of natural killer cells rebounded later than patients with conventional types of natural killer cells. Natural killer cells are a type of immune cell that is normally thought to destroy virus-infected cells. But they also help regulate the actions of other immune cells, which may influence HIV rebound after treatment.
“Taken together, our findings suggest that there is probably no single solution to controlling HIV,” says Dr. Ashley George, a research scientist at Gladstone and co-lead author of the study. “By harnessing the different characteristics of immune cells that help fight infection, we may have multiple opportunities to control HIV without the need for ART.”
Trialable results for metformin
The study’s most impressive findings came from a subset of patients’ CD4+ T cells, the main cell type that acts as a reservoir for HIV.
People whose storage cells had higher levels of two specific genes, DDIT4 and ZNF254, tended to have longer HIV rebound times after stopping antiretroviral therapy. In follow-up lab experiments, Roan and her team confirmed that both genes can suppress HIV.
“Both genes represent potential new targets for a promising ‘block-and-lock’ strategy to cure HIV, in which drugs would first be used to block HIV activation, and then methods would be used to make this block permanent,” says George.
This approach is the primary focus of the HIV Inhibition Through Programmed Epigenetics (HOPE) Collaboratory. The HOPE Collaborative is an interdisciplinary group of researchers, including Roan and other co-authors of the new study, working on a cure for HIV.
Upon further analysis of the publicly available data, the team found even more supporting evidence. They found that people with higher levels of the two genes had reduced HIV activity in their cells. And “elite controllers” (people whose bodies naturally suppress HIV from the beginning of infection, even without treatment) have much higher levels of the gene ZNF254 in their CD4+ T cells.
“One of the possibilities we envision in the future is that we could somehow deliver ZNF254 into infected cells and turn people into elite managers,” George says. “We can also try to manipulate even more powerful versions of this gene.”
But of all the new study’s findings, the link between the gene DDIT4 and delayed rebound may have the most direct impact on patients. That’s because levels of this gene can be increased by the drug metformin, which has already been observed in non-immune cells by the scientific community, and this study showed that it also applies to T cells.
This led scientists to conduct a series of experiments to test whether metformin could help suppress HIV. In one notable experiment, treating cells from HIV-infected people with metformin blocked the ability of HIV to reactivate, suggesting a possible role for the drug in helping achieve a “block and lock.”
The research team will next test metformin and related compounds in various preclinical models for their ability to prevent HIV-retaining cells from producing active HIV upon discontinuation of antiretroviral therapy.
Drugs that effectively suppress HIV may also provide health benefits for people continuing antiretroviral therapy. This is because the drugs can limit the levels of viral gene products (driving forces of inflammation) to which these people are chronically exposed.
“We are excited to pursue HIV silencing strategies not only as a way to achieve block and lock, but also as a strategy to improve the overall health of HIV-infected people by reducing chronic inflammation,” says Roan.
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Reference magazines:
Ma, T, others. (2026). Multiohmic analysis of an ART discontinuation cohort identifies extracellular and intrinsic mechanisms that drive lymphocyte-mediated HIV rebound control. immunity. DOI: 10.1016/j.immuni.2026.01.029. https://www.cell.com/immunity/fulltext/S1074-7613(26)00049-X.
