Antidiabetic drug may help reduce persistent inflammation in people living with HIV

Metformin, a drug used to treat type-2 diabetes, may help reduce persistent inflammation in people living with HIV (PLWH) who are being treated. treatment with antiretroviral therapy (ART), according to researchers at the University of Montreal Hospital Research Center (CRCHUM).

Although ART has helped improve PLWH health, they are at greater risk of developing complications associated with chronic inflammation, such as cardiovascular disease. These health problems are largely due to the survival of HIV reservoirs in the long-term T memory cells of patients and due to the constant activity of their immune system.

In a recently published pilot study in EBioMedicine (URL), professor of immunology Université de Montréal Petronela Ancuta and first author Delphine Planas, a PhD student in her laboratory at the CRCHUM, evaluates the ability of metformin to enhance immune function and reduce viral reservoir size.

We asked Professor Ancuta to explain the study.

C. Despite the use of antiretroviral therapy, seropositive people exhibit immune activity and excessive inflammation. In your study, you try to stop that with metformin. How come?

Currently, antiretroviral therapies inhibit HIV reproduction by preventing the introduction of virion (full viral grain) into new cells and the exit of infectious cells. However, one step has yet to be targeted by these therapies: proliferation of the viral genome within the infectious cell.

Despite antiretroviral therapy, this intracellular viral proliferation causes harmful inflammation and immune activity, leading to the emergence of co-infections such as cardiovascular disease. In the laboratory, we are working to identify new therapies to prevent intracellular viral proliferation.

The idea for metformin use in people living with HIV came from Dr.?Jean-Pierre Routy of the McGill University Health Center Research Institute, our colleague in this study. Widely used in medicine, this drug stimulates or inhibits the reactions of the body’s immune system.

In our study, knowing that metformin affects the molecular activity of mTOR (mechanical target of rapamycin) involved in intracellular proliferation of the HIV genome, we used the drug to treat 22 nondiabetic PLWH on antiretroviral therapy (13 in Montreal and nine in Ottawa). In vitro, studies by our group and others have previously shown that inhibition of mTOR by drugs significantly inhibits HIV reproduction in the cells of patients infected with the virus.

Q. Were you surprised by the results of your study?

Yes, we were thrilled with the positive results of this pilot study. The drug was highly tolerated by the patients and we saw the beneficial biological effects of metformin in colon biopsies.

HIV hides in CD4 T cells, cells of the immune system that secrete the virus and form viral reservoirs in a number of peripheral glands such as the gut. The virus continues to grow in these reservoirs and lead to inflammation.

In the study, we observed a decrease in mTOR activity in CD4 T cells present in the colon, as well as a decrease in some signs of plasma inflammation and intestinal damage. Metformin, therefore, has both intestinal and systemic effects.

C. The size of an HIV reservoir is related to the rate of inflammation. Could new approaches like yours reduce the size of these reservoirs? Have you looked at this in your study?

The size of the viral DNA reservoir in T blood cells and in the colon was very stable, which is consistent with the known stability of HIV reservoirs. However, we anticipate that prolonged treatment may lead to a reduction in these reservoirs. This hypothesis is worth proving.

Q. Did you continue your research with a larger patient sample?

We are going to launch a new randomized study of more than 58 participants in which metformin will be administered over a longer period of time. We plan to do it over six to 12 months to test the benefits of metformin in controlling inflammation, in part by regulating mTOR.

To conclude, I would like to thank the participants in the LILAC study for providing their biological samples and for believing in our research efforts, which resulted in thanks to so -worked closely with many researchers, particularly Drs. Jean-Pierre Routy and Maged Peter Ghali (McGill University Health Center), Nicolas Chomont (CRCHUM) and Dr.?Jonathan Angel (Ottawa Hospital Research Institute).