Diabetes drug may be a new weapon against HIV

A team led by scientists from the UNC School of Medicine has discovered a significant vulnerability of the HIV retrovirus responsible for AIDS and has shown in preclinical experiments that a widely used diabetes drug, metformin, appears capable of ‘exploit this vulnerability.

Scientists, whose study is published in Nature’s immunology, discovered that HIV, when it infects immune cells called CD4 T cells, helps fuel its own replication by stimulating a key process in the chemical energy production of cells. They also found that metformin, a diabetes drug, inhibits the same process and thus suppresses HIV replication in these cells, both in cell culture experiments and in mice.

“These results suggest that metformin and other drugs that reduce T cell metabolism may be useful as adjunct therapies for the treatment of HIV,” said study co-lead author Haitao Guo, Ph .D., Assistant Professor in the Department of Genetics of UNC at UNC. Medicine School.

The co-first author of the study was Qi Wang, Ph.D., postdoctoral research associate. The study’s co-lead authors were Jenny Ting, Ph.D., William R. Kenan, Jr., distinguished professor in the Department of Genetics at UNC-Chapel Hill, and Lishan Su, Ph.D., professor of pharmacology at the University. of the Maryland School of Medicine and formerly of the UNC School of Medicine.

About 38 million people worldwide are living with HIV infection, according to the most recent estimates from the World Health Organization. Doctors are currently treating these infections with combinations of antiretroviral drugs to suppress HIV replication.

However, many patients despite this treatment show signs of residual viral replication and immune deficiency. Even patients who respond well to antiretroviral drugs have to take them indefinitely, because HIV becomes embedded in the DNA of some infected cells and drugs cannot remove this viral genetic “reservoir”. In addition, the toxicity of anti-HIV drugs means that many patients can only take them intermittently. Thus, despite the progress, there is still a lot to be done in the treatment of HIV.

A possible new approach to treating HIV is not to attack it directly, but to make the cells it infects less conducive to viral replication. For example, other research has shown that HIV stimulates the production of energy in CD4 cells, apparently to improve the ability of the virus to replicate in these cells. Guo and his colleagues in their study sought to better understand how HIV does this and whether reversing this metabolic effect could suppress HIV.

Together with Rafick-Pierre Sekaly, Ph.D., and Khader Ghneim of Case Western University, they analyzed CD4 cell gene expression data from a study of people infected with HIV in Africa and Asia. and found that the gene expression patterns most closely linked to poor outcomes in these patients involved an energy-producing process called oxidative phosphorylation.

They then found that drugs and other chemicals that inhibit oxidative phosphorylation in CD4 cells can inhibit HIV’s ability to replicate in these cells. One of these drugs is the diabetes drug, metformin, which is one of the most prescribed drugs in the world, is considered safe and well tolerated, and is also inexpensive. Guo and his colleagues have confirmed by further experiments on primary human CD4 cells and in mice with human CD4 cells, that metformin suppresses HIV replication in these cells.

The researchers also looked at an earlier study of HIV patients on antiretroviral therapy to find that after six months of treatment, patients with type 2 diabetes – many of whom were said to have taken metformin – had an average 33% rate. lower HIV levels in the blood, compared to non-diabetic patients in the cohort. Diabetic patients also had, on average, higher baseline CD4 cell counts and faster recoveries from these levels with antiretroviral therapy.

“These real-world findings are consistent with the idea that metformin has a significant anti-HIV effect,” Ting said.

Scientists ultimately traced HIV’s ability to increase oxidative phosphorylation in CD4 cells to its increased levels of NLRX1, a protein associated with mitochondria – tiny oxygen reactors that help cells produce the chemical energy they have. need. NLRX1 appears to be a key metabolic switch that HIV uses to enhance its replication in CD4 cells, making it a potential target for future anti-HIV treatments.

“This work shows the importance of CD4 cell metabolism in HIV, and suggests that it can be targeted, for example with reused drugs such as metformin, to reduce the viral load of HIV and restore these fighting CD4 cells. disease, ”Ting said.

Researchers plan to continue preclinical studies on the potential of metformin as an anti-HIV treatment, possibly a therapy that could reduce the need for toxic antiretrovirals and could be given to patients earlier to reduce the formation of HIV reservoirs. . They note that Canadian researchers, using very different reasoning – that metformin may help preserve CD4 cells by changing the makeup of gut bacteria to reduce inflammation and chronic T cell activation – conducted a clinical trial on metformin in non-diabetic HIV patients, but have not yet published results on its effectiveness in improving markers of HIV infection.