Metformin is commonly used to help people with type 2 diabetes manage their blood sugar levels. The diabetes drug is derived from a lilac plant that’s been used medicinally for more than a thousand years. For most patients, metformin works to bring down blood sugar gradually when combined with a healthy diet and exercise. Metformin has also been shown to helping treat ailments other than diabetes, such as reversing inflammation in the liver. Researchers are currently studying whether the medicine can help in the fight against cancer, neurodegenerative conditions, vision problems like macular degeneration, and even aging; HIV may be added to the list, as a new study demonstrates how metformin seems to exploit HIV’s weak spot.
Their findings, “Multi-omics analyses reveal that HIV-1 alters CD4+ T cell immunometabolism to fuel virus replication,” were published in the journal Nature Immunology. The study was led by scientists at the UNC School of Medicine.
“Individuals infected with human immunodeficiency virus type-1 (HIV-1) show metabolic alterations of CD4+ T cells through unclear mechanisms with undefined consequences,” wrote the researchers. “We analyzed the transcriptome of CD4+ T cells from patients with HIV-1 and revealed that the elevated oxidative phosphorylation (OXPHOS) pathway is associated with poor outcomes. Inhibition of OXPHOS by the FDA–approved drug metformin, which targets mitochondrial respiratory chain complex-I, suppresses HIV-1 replication in human CD4+ T cells and humanized mice.”
The scientists found that when HIV infects immune cells called CD4+ T cells, it helps fuel its own replication by boosting a key process in the cells’ production of chemical energy. Metformin inhibits the same process and suppresses HIV replication in these cells.
“These findings suggest that metformin and other drugs that reduce T-cell metabolism might be useful as adjunct therapies for treating HIV,” explained study co-first author Haitao Guo, PhD, assistant professor in the UNC department of genetics at the UNC School of Medicine.
To come to this finding, the researchers sought to understand better how HIV boosts CD4 cell energy production, and whether reversing this metabolic effect could suppress HIV. In collaboration with Rafick-Pierre Sekaly, PhD, and Khader Ghneim at Case Western University, the researchers analyzed CD4-cell gene expression data from a study of HIV-infected people in Africa and Asia and found that the gene-expression patterns most closely related to poor outcomes among these patients involved an energy-production process called oxidative phosphorylation.
They found drugs and other chemical compounds that inhibit oxidative phosphorylation in CD4 cells, one of them being metformin. Further experiments in primary human CD4 cells, and in mice with human CD4 cells, confirmed that metformin suppresses HIV replication in these cells.
The researchers also examined a prior study of HIV patients taking antiretroviral therapy to discover that, after six months of treatment, the patients that had type 2 diabetes—many of whom would have been taking metformin—had on average 33% lower levels of HIV in the blood, compared with non-diabetic patients in the cohort. The diabetic patients also, on average, had higher baseline CD4 cell levels and quicker recoveries of these levels with antiretroviral treatment.
“Those real-world findings are consistent with the idea that metformin has a significant anti-HIV effect,” explained co-senior author Jenny Ting, PhD, the William R. Kenan, Jr., distinguished professor, genetics, UNC School of Medicine.
The researchers traced HIV’s ability to increase oxidative phosphorylation in CD4 cells to its boosting of the levels of NLRX1, a protein associated with mitochondria. NLRX1 appears to be a key metabolic switch that HIV uses to enhance its replication in CD4 cells, which in turn makes it a potential target for future HIV treatments.
“This work shows the importance of CD4 cell metabolism in HIV, and suggests that it may be targetable, for example, with repurposed drugs such as metformin, to reduce HIV viral load and restore these disease-fighting CD4 cells,” Ting said.
The researchers are planning to continue preclinical studies of metformin’s potential as an anti-HIV treatment.