New research reveals how immune cells, key genes, and metformin may help delay HIV rebound, offering fresh insights into long-term HIV control without continuous treatment.
For years, HIV treatment has relied on one unchanging rule: stop the medication, and the virus returns – often within weeks. But scientists are now beginning to understand why a small group of individuals can keep HIV suppressed long after treatment ends. And the answers may open the door to a future with fewer pills, or even long-term remission.
In a recent study published in Immunity, researchers from the Gladstone Institutes uncovered a combination of immune cell behaviour, genetic “locks”, and a widely used diabetes drug that may help maintain HIV’s dormant state after treatment stops, suggesting a possibility of long term control of the once-feared condition.
Why Does HIV Usually Come Back?
Antiretroviral therapy (ART) is the standard treatment for HIV. It involves a combination of medications taken daily to suppress the virus, preventing it from multiplying in the body. While highly effective at suppressing HIV, it does not eliminate the virus completely. Instead, HIV hides in so-called “reservoir” cells where it can remain inactive but intact.
This reduces the viral load to undetectable levels, allowing people to live long, healthy lives and significantly lowering the risk of transmission.
However, if treatment is interrupted, these hidden reservoirs can reactivate, allowing the virus to multiply again and potentially progress to Acquired Immunodeficiency Syndrome (AIDS).
In rare cases, some individuals experience a much slower viral rebound, sometimes taking months or even years, and this has been of interest in HIV research.
The Immune System’s Role in Delaying HIV Rebound
In the study, Nadia Roan, PhD, senior investigator at Gladstone Institutes and her colleagues analysed blood samples from 75 participants across four clinical trials. All of these participants had paused HIV treatment under close supervision.
By collecting blood samples just before treatment stopped and measuring gene and protein activity, the team sought to identify patterns of interest.
They found that certain immune cells appear to play an important role in delaying the virus’s return.
Firstly, individuals with higher levels of stem cell memory CD8+ T cells appeared to experience slower viral return. Notably, the two participants showing the longest delays – over 22 weeks and over 33 weeks – also had the highest levels of these cells.
“These CD8+ T cells appear to have ‘stem-like’ features and might be able to stick around to continue replenishing themselves for prolonged periods of time, which may help them contribute to long periods of ART-free HIV control,” Roan says.
Another finding pointed to natural killer (NK) cells. While these cells are known for destroying infected cells, some variants may also influence how other immune cells function. Hence, they may affect broader immune responses and contribute to slower HIV reactivation.
The researchers also identified important changes in CD4+ T cells, the main type of cell that serves as an HIV reservoir.
Genetic “Locks” That Keep HIV Dormant
Beyond immune cells, researchers identified two genes – DDIT4 and ZNF254 – that appear to act like internal ‘locks’ within infected cells. Higher levels of these genes were associated with reduced viral activity and delayed rebound after treatment interruption. Laboratory experiments confirmed that both genes can actively suppress HIV activity, keeping the virus in a dormant state.
This supports a promising strategy in HIV research known as “block and lock”, where the goal is not to eliminate the virus entirely, but to permanently silence it. The drugs first ‘block’ HIV activation. Then they ‘lock’ it by making this block permanent. Notably, this strategy is central to the work of the HIV Obstruction by Programmed Epigenetics (HOPE) Collaboratory, a research group focused on finding a cure.
What does the discovery of these genes mean?
“One possibility we’re imagining for the future is that we could somehow deliver ZNF254 to infected cells,” Ashley George, PhD, research scientist at Gladstone says. “We could also try to engineer an even stronger version of this gene.”
Among all the findings, the link between DDIT4 and delayed viral return may have the most immediate clinical relevance. Levels of this gene can be increased by metformin, something previously observed in other cell types. Now this has been confirmed in T cells by this study.
The Link Between Metformin and HIV
Researchers have found that metformin can increase levels of DDIT4 in T cells, one of the key genes linked to HIV suppression. In past studies, the increase in DDIT4 was observed in other cell types. Furthermore, in laboratory experiments, metformin also directly prevented HIV from reactivating in infected cells.
This is an exciting revelation as it raises the possibility that a common, well-understood and relatively safe medication like metformin could bear new purpose in helping to delay or even prevent HIV rebound in patients.
While this is still at an early stage, the team is now exploring further preclinical and clinical studies to test this potential.
What This Means for the Future of HIV Research and Care
“Altogether, our findings suggest there’s probably not just one solution for suppressing HIV,” says Ashley George, PhD, research scientist at Gladstone and co-first author on the study. “By leveraging different features of immune cells that can help fight infection, we likely have multiple opportunities to control HIV without the need for ART.”
With the exploration of these factors in HIV research moving forward, especially in the realm of delaying HIV rebound, this could eventually translate into longer periods without daily medication. It could even mean a possibility of long-term remission without medication.
Current treatment guidelines remain unchanged, and antiretroviral therapy is essential for managing HIV safely.
