For millions living with HIV, daily antiretroviral therapy (ART) is a lifelong necessity. Stopping these medications typically leads to a rapid resurgence of the virus within weeks. However, a little, intriguing group of individuals experiences a different outcome: their viral load remains controlled for months, even years, after discontinuing treatment. Now, researchers are beginning to unravel the biological mechanisms behind this natural suppression, potentially paving the way for a “block and lock” strategy that could offer a functional cure for HIV.
The key to understanding this phenomenon, according to a recent study published in the journal Immunity, may lie in specific immune cells and the genes they express. Scientists at the Gladstone Institutes, led by senior investigator Nadia Roan, PhD, have identified two genes within infected cells that appear to act as “security locks,” keeping the virus in a dormant state. Perhaps even more promising, their research suggests that metformin, a widely used and affordable medication for type 2 diabetes, can activate one of these locks, bolstering the body’s natural ability to control HIV.
“Our data suggest metformin might be able to delay, or possibly even prevent HIV rebound in some individuals, which is exciting because it’s a extremely safe and affordable drug,” said Dr. Roan. “We are now very interested in pushing forward with pre-clinical and eventually clinical studies to directly test these potential benefits.”
Unlocking the Secrets of Natural HIV Control
The challenge in curing HIV lies in the virus’s ability to establish “reservoirs” – hidden stores of infected immune cells where the virus lies dormant. Even with ART effectively suppressing viral replication in the bloodstream, these reservoirs persist. When treatment is stopped, the virus can reactivate from these reservoirs, leading to a return of symptoms and, if left untreated, progression to AIDS. According to the Centers for Disease Control and Prevention, approximately 1.2 million people in the United States are living with HIV, and approximately 13% are unaware of their infection. CDC HIV Statistics
To pinpoint the factors that allow some individuals to maintain viral control off ART, Dr. Roan and her team analyzed data from four clinical trials where participants intentionally stopped their HIV medication – often as part of studies evaluating potential cures. They collected blood samples from 75 participants before they paused treatment, meticulously measuring gene and protein levels within various immune cells to identify correlations between these features and the time it took for HIV to rebound.
The analysis revealed several key findings. Higher levels of a specific type of immune cell, stem cell memory CD8+ T cells, were associated with delayed viral rebound in two of the trials. Notably, the two patients with the most prolonged periods of viral control – exceeding 22 and 33 weeks, respectively – also exhibited 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,” Dr. Roan explained.
Further investigation showed that individuals with an atypical form of natural killer (NK) cells also experienced delayed viral rebound. While NK cells are traditionally known for destroying virus-infected cells, they also play a regulatory role in immune function, potentially influencing post-therapy HIV control. Ashley George, PhD, a research scientist at Gladstone and co-first author on the study, emphasized that “all together, our findings suggest there’s probably not just one solution for suppressing HIV. 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.”
Metformin and the “Block and Lock” Strategy
The most striking discoveries centered on CD4+ T cells, the primary target and reservoir for HIV. Researchers found that individuals whose reservoir cells had higher levels of two specific genes, DDIT4 and ZNF254, experienced longer delays in viral rebound after stopping ART. Follow-up laboratory experiments confirmed that both genes possess the ability to suppress HIV replication.
“Both genes represent possible new targets for a promising ‘block and lock’ strategy for curing HIV, in which drugs would first be used to block HIV activation, followed by ways to make this block permanent,” Dr. George stated. This approach is a central focus of the HIV Obstruction by Programmed Epigenetics (HOPE) Collaboratory, a multidisciplinary research group dedicated to finding an HIV cure.
Analyzing publicly available data, the team found that individuals with higher levels of DDIT4 and ZNF254 exhibited reduced HIV activity within their cells. Interestingly, “elite controllers” – individuals whose immune systems naturally suppress HIV without medication – demonstrated significantly higher levels of the ZNF254 gene in their CD4+ T cells. “One possibility we’re imagining for the future is that we could somehow deliver ZNF254 to infected cells in order to turn people into elite controllers,” Dr. George suggested. “We could also try to engineer an even stronger version of this gene.”
However, the link between DDIT4 and delayed rebound holds the most immediate promise. Levels of DDIT4 can be increased by metformin, a finding previously observed in non-immune cells, and now confirmed within T cells by this study. Experiments demonstrated that treating HIV-infected cells with metformin blocked viral reactivation, suggesting a potential role for the drug in achieving a “block and lock” effect.
The research team is now planning pre-clinical studies to evaluate metformin and related compounds for their ability to prevent HIV reservoir cells from generating active virus when ART is interrupted. Beyond a potential cure, effectively silencing HIV could also improve the overall health of individuals on ART by reducing chronic inflammation, a common consequence of persistent viral activity.
“We are excited to pursue HIV silencing strategies both as a way to achieve block and lock, but also as a strategy to improve the overall health of people with HIV by lessening chronic inflammation,” Dr. Roan concluded.
Source:
Journal reference:
Ma, T., et al. (2026). Multiomic analysis of ART-interruption cohorts identifies cell-extrinsic and -intrinsic mechanisms driving lymphocyte-mediated control of HIV rebound. Immunity. DOI: 10.1016/j.immuni.2026.01.029. https://www.cell.com/immunity/fulltext/S1074-7613(26)00049-X.
Disclaimer: This article is for informational purposes only and should not be considered medical advice. Consult with a qualified healthcare professional for any health concerns or before making any decisions related to your health or treatment.
The next step in this research will be pre-clinical trials to assess the efficacy of metformin and related compounds in preventing HIV reactivation. The results of these studies will be crucial in determining whether this promising “block and lock” strategy can be translated into effective therapies for people living with HIV.
What are your thoughts on this new research? Share your comments below, and please share this article with your network.
