Diabetes drug helps immune system recognize HIV reservoirs, study finds

Metformin, a drug used to treat type 2 diabetes, may help deplete the viral reservoir and eliminate it completely in people living with HIV who are receiving antiretroviral therapy, Canadian researchers say in a new study.

In 2021, a team led by immunologist Petronela Ancuta from the Research Center of the Hospital Research Center affiliated with the University of Montreal (CRCHUM), demonstrated that metformin, taken for three months, improved patients’ immunity and reduced chronic inflammation usually associated with complications such as cardiovascular disease.

One reason these benefits are so effective is that metformin inhibits the activity of the molecule mTOR (mechanistic target of rapamycin), which in turn slows HIV replication in the cells of patients infected with the virus.

In the newspaper iScienceAncuta and his student Augustine Fert, the study’s first author and a recent PhD graduate, went further. They studied the molecular mechanisms of how metformin affects HIV replication in CD4 T cells, cells in the immune system that harbor the virus.

In these reservoirs, HIV continues to replicate, contributing to chronic inflammation by constantly activating the immune system.

“The results of our in vitro tests on cells from people living with HIV and treated with antiretrovirals initially took us by surprise,” Ancuta said. “They were a bit surprising. We found that metformin had both a proviral and an antiviral effect. The drug helped increase the number of HIV-infected cells, while preventing the virus from escaping from the cell.”

Antibodies to the rescue

Another advantage of metformin is that it overexpresses the protein BST2, which acts like a glue to keep virions attached to the surface of HIV-infected cells. The immune system then spots them and can target them with antibodies.

“With my colleague Andrés Finzi, we tested the ability of several broad-spectrum neutralizing anti-HIV antibodies to recognize viral reservoir cells after exposure to metformin in vitro,” Ancuta said. “Some of them recognized the virus very well, suggesting their ability to attract and trigger the destruction of infected cells by NK cells through a process of cellular cytotoxicity.”

These recent scientific advances mean that the “shock and die” eradication strategy often used in the fight against HIV can be approached in a different way, she added.

“In people living with HIV and treated with antiretroviral therapy, we could use metformin to reactivate the reservoir cells responsible for viral replication when treatment is interrupted, in combination with antibodies already used in the clinic and well tolerated. These antibodies can then detect the rare infected cells and eliminate them.”

In the next phase of its research, Ancuta plans to launch a clinical trial to validate the results of its in vitro research, in collaboration with Finzi and their CRCHUM colleague Nicolas Chomont, and Jean-Pierre Routy of the Research Institute of the McGill University Health Centre.

Before she can move forward with this strategy, she will test it in preclinical models.

Provided by the Research Center of the University of Montreal Hospital Center