Metformin: From Diabetes Treatment to a New Approach for HIV Cure

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Metformin: From Diabetes Treatment to a New Approach for HIV Cure

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Metformin: From Diabetes Treatment to a New Approach for HIV Cure

While antiretroviral therapy (ART) effectively controls HIV viral replication, eliminating the virus entirely remains a challenge due to the persistence of latent viral reservoirs in the body.

Recently, some media have reported that metformin, a drug traditionally used to treat diabetes, may play a significant role in reactivating and clearing these viral reservoirs.

Metformin not only helps regulate metabolism but also enhances the immune system’s ability to recognize these reservoirs. So, what exactly is metformin, and how does it aid in immune modulation and viral reservoir activation? Let’s explore this further.

What is Metformin?

Metformin is a commonly prescribed oral medication for type 2 diabetes, used since 1957. It works by reducing the liver’s production of glucose, increasing the body’s sensitivity to insulin, and helping muscles absorb glucose more effectively.

It is often the first-line treatment for type 2 diabetes, particularly for overweight or obese patients. Additionally, it’s used to treat other conditions, such as polycystic ovary syndrome (PCOS).

Metformin is generally well-tolerated, with gastrointestinal side effects like diarrhea and nausea being the most common, though these usually improve over time.

Recently, researchers have focused on metformin’s effects on HIV-1 patients due to its potential in metabolic regulation and immune function enhancement.

Metformin’s Role in Modulating HIV Patients’ Immune Function

• Effects on CD8 Cells: Studies show that metformin can significantly enhance CD8+ T cell function in HIV-1 patients, improving their antiviral capabilities. In particular, at a concentration of 800 µM, the secretion of the antiviral factor IFN-γ by CD8+ T cells reached its peak, suggesting that metformin could help strengthen HIV-specific immune responses.

• Protection of CD4 Cells: CD4+ T cells are crucial in maintaining immune system function, but their numbers decline in HIV patients. Research has demonstrated that metformin can reduce CD4+ T cell death caused by caspase-1, thereby preserving these vital immune cells.

• Suppression of Monocytes: HIV patients often experience chronic inflammation, especially those not on ART. Metformin significantly suppresses the release of pro-inflammatory cytokines like TNF-α and IL-6, helping to reduce chronic inflammation and lower the risk of HIV-related complications, such as cardiovascular disease and neurocognitive disorders.

How Does Metformin Influence the Reactivation of HIV Reservoirs?

• Promoting Reactivation: Metformin increases the number of activated CD4+ T cells, though this does not necessarily correlate with a proportional increase in viral release. By boosting levels of proteins like BST2 and Bcl-2, metformin aids in reactivating cells in the viral reservoir, making them more recognizable to the immune system.

• Enhancing Antibody Recognition: Metformin also enhances the ability of anti-HIV-1 envelope antibodies, such as PGT126, to recognize reactivated viral reservoir cells. This supports antibody-dependent cytotoxic responses, potentially accelerating the clearance of these reservoirs.

• Impact on Viral Replication: Although metformin does not promote the integration of viral DNA, it stimulates infected cells to produce new viral particles, making them visible to the immune system for destruction.

• Preserving Th17 Cells: Th17 cells play a crucial role in fighting infections. Metformin supports the expression of markers related to Th17 polarization, helping maintain their function, which is vital for immune responses against HIV.

Could Metformin Lead to New Advances in HIV Treatment?

HIV cure research focuses on two main approaches: identifying and destroying latent viral reservoirs (“shock-and-kill” strategy) or permanently silencing the virus (“functional cure”). While metformin’s multiple roles in HIV patients have been preliminarily confirmed, further studies are required to determine its clinical potential.

One notable mechanism is metformin’s ability to promote the overexpression of BST2, a protein that “glues” viral particles to the surface of infected cells. This makes it easier for the immune system to recognize and target these cells through antibody responses.

Researchers have also been exploring combination therapies involving broadly neutralizing antibodies (bNAbs). A recent study introduced a triple antibody regimen, combining PGT121, PGDM1400, and VRC07-523LS, which covers 99% of global HIV strains and significantly enhances antiviral efficacy.

These findings suggest that traditional “shock-and-kill” strategies might be enhanced by combining metformin with antibody-dependent cytotoxic responses. This could pave the way for more effective methods to clear HIV reservoirs in the future.

Metformin: From Diabetes Treatment to a New Approach for HIV Cure

References:

1. Fert, A., Richard, J., Marchand, L. R., et al. (2024). Metformin facilitates viral reservoir reactivation and their recognition by anti-HIV-1 envelope antibodies. iScience, 27(9), 110670. https://doi.org/10.1016/j.isci.2024.110670
2. Liu, F., Wu, F., Dai, X., et al. (2021). Study on the effects of metformin on immune cell function in HIV-1 infected patients. Chinese Journal of AIDS & STD, 27(6), 570-576.

(source:internet, reference only)

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Important Note: The information provided is for informational purposes only and should not be considered as medical advice.