Metformin, a widely prescribed medication for type 2 diabetes, may offer a novel approach to targeting HIV reservoirs in individuals undergoing antiretroviral therapy. Researchers at the University of Montreal Hospital Research Centre (CRCHUM) have discovered that metformin enhances the immune system's ability to recognize and eliminate HIV-infected cells, potentially contributing to viral eradication.
Metformin's Dual Action on HIV Replication
The study, published in iScience, builds upon previous work demonstrating metformin's ability to improve immunity and reduce chronic inflammation in HIV patients. The researchers, led by immunologist Petronela Ancuta, found that metformin inhibits the mechanistic target of rapamycin (mTOR) molecule, which slows down HIV replication. Further investigation revealed a dual action of metformin on CD4 T lymphocytes, the immune cells that harbor HIV. While the drug increased the number of HIV-infected cells, it also prevented the virus from escaping these cells.
"The results of our in vitro tests on cells from people living with HIV and treated with antiretroviral therapy caught us off guard at first," said Ancuta. "They were a bit surprising. We discovered that metformin had both a proviral and an antiviral effect. The drug helped boost the number of HIV-infected cells, while also stopping the virus from escaping the cell."
Enhancing Antibody Recognition Through BST2 Overexpression
A key finding of the study is metformin's ability to overexpress the BST2 protein. BST2 acts as a "glue," causing virions to adhere to the surface of HIV-infected cells. This allows the immune system to more easily detect and target these cells with antibodies. In collaboration with Andrés Finzi, the team tested the ability of broad-spectrum neutralizing anti-HIV antibodies to recognize viral reservoir cells after metformin exposure. The results showed enhanced recognition, suggesting the potential for NK cells to destroy infected cells through cellular cytotoxicity.
Implications for HIV Eradication Strategies
These findings have significant implications for the "shock-and-kill" strategy, which aims to reactivate latent HIV reservoirs and then eliminate the infected cells. Metformin could be used to reactivate reservoir cells in combination with clinically available and well-tolerated antibodies, facilitating the detection and elimination of these cells. Ancuta plans to launch a clinical trial to validate these in vitro results, in collaboration with Finzi, Nicolas Chomont, and Jean-Pierre Routy.
"In people living with HIV and treated with antiretroviral therapy, we could use metformin to reactivate the reservoir cells responsible for viral replication upon treatment interruption, in combination with antibodies that are already used clinically and well tolerated. These antibodies can then detect the rare infected cells and eliminate them."
Before initiating the clinical trial, the strategy will be tested in preclinical models to further assess its safety and efficacy.
