Metformin reduces HHV-6A replication in T cells by activating AMPK

Conversely, HHV-6A infection increases viral replication by inhibiting AMPK and enhancing mTOR signaling and glycolysis.

Adenosine monophosphate-activated protein kinase (AMPK) is a master metabolic sensor of cellular energy homeostasis, acting as a negative regulator of the mammalian target of rapamycin (mTOR) signaling pathway. The mTOR pathway integrates both intracellular and extracellular signals and serves as a central regulator of cell metabolism, growth, proliferation and survival.

When AMPK senses stress, it inhibits the mTOR pathway. This, in turn, inhibits energy-consuming anabolic pathways—such as fatty acid and sterol synthesis—while enhancing energy-producing catabolic pathways—such as fatty acid oxidation.  Activated AMPK phosphorylates many downstream substrates that are important in metabolism, autophagy, innate immune signaling and mitochondrial biogenesis.

Previous studies have found that AMPK signaling may play an important role in some viral infections – i.e., Zika virus, dengue virus (Farfan-Morales 2021), SARS CoV-2 (Parthasarathy 2023) and CMV (McCardle 2012). For example, by inactivating AMPK, HHV-6A increases mTOR signaling and increases glycolysis which, in turn, enhances the replication of HHV-6A.

Investigators at Nanjing Medical University examined the impact of HHV-6A infection on AMPK and mTOR signaling. Two cell lines were used: the human T-lymphoblastoid cell line HSB-2 and umbilical cord mononuclear cells (CBMCs).  These cell lines were either mock infected or infected with HHV-6A, and the consequences examined 72 hours later.

Infection with HHV-6A, but not with UV-irradiated HHV-6A, inhibited AMPK activity and thereby increased glycolysis, consistent with prior findings. Conversely, chemical activation of AMPK by metformin, aminoimidazole carboxamide ribonucleotide (AICAR), or by compound GSK621 inhibited the replication of HHV-6A and decreased glycolysis as a result of decreasing the expression of several key glycolytic enzymes.  These findings are summarized in Figure 1. 

Figure 1: HHV-6A infection reduces AMPK activity, which leads to activation of mTOR signaling and enhancement of glycolysis. Pharmacological activation of AMPK by AICAR or metformin significantly reduces HHV-6A-mediated glycolytic activation and impairs mTOR signaling, and then inhibits virus propagation. AICAR had a toxic impact on CMBCs, but metformin had no impact on cell viability after three days of treatment.

This report extends previous findings by demonstrating the important role played by the AMPK-mTOR signaling pathways in the replication of HHV-6A.  It also suggests ways by which HHV-6A replication might be inhibited pharmacologically, by an indirect activators of AMPK such as metformin, or direct agonists such as as GSK21. 

Read the full article: Yang 2024