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Metformin suppresses human CMV infection
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Does CMV Suppression Explain Metformin's Age-Slowing Effect?
8th International Workshop on HIV and Aging, October 2-3, 2017, New York
Mark Mascolini
Metformin, a first-line antihyperglycemic for type 2 diabetes, has also accrued a reputation for its "geroprotective" effects [1,2], noted Johns Hopkins researchers who conducted this study [3]. But the mechanisms behind these antiaging properties remain poorly understood. The Hopkins group focused their inquiry on metformin inhibition of human cytomegalovirus (HCVM).
The researchers reminded colleagues that latent or chronic CMV affects a high proportion of people with HIV. A herpesvirus, CMV furthers several potentially age-related processes, including T-cell immunosenescence, chronic inflammation, and immune activation. CMV also ranks as a risk factor for cardiovascular disease, frailty, disability, and mortality.
The Hopkins investigators aimed to test the hypothesis that metformin suppresses HCMV replication and protein expression in human fibroblasts. They inoculated HCMV into MRC-5 human fibroblast cultures at a low multiplicity of infection (MOI) of 0.01. The researchers noted this low MOI mimics chronic HCVM infection in people without immunodeficiency and usually yields an undetectable CMV level in serum or plasma. Two hours before HCVM inoculation, they exposed the fibroblasts to 0.5, 1, 3, or 5 mM of metformin, and they cultured the cells for up to 5 days after infection.
The researchers measured HCMV-induced cytopathic effect by viral plaque formation, and they gauged HCMV replication by quantitative PCR. Western blots assessed HCMV protein expression.
Three and 5 days after infection, metformin suppressed HCMV-induced cytopathic effect, with best results at the 3 mM dose. The drug suppressed HCMV replication in a concentration-dependent manner: Viral copy number fell an average 70% with the 0.5 mM concentration, 80% with 1 mM, and more than 90% with 3mM or 5mM. Two, 3, and 5 days after infection, metformin at the 3-mM dose reduced HCVM replication more than 85%.
Metformin at the lowest concentration, 0.5 mM, completely suppressed expression of the HCMV late protein pp28. The antihyperglycemic suppressed expression of HCMV immediate early 2 protein and delayed expression of the pp52 protein in a dose-dependent manner. Metformin also exerted suppressive effects on HCMV infection at MOIs up to 1.0.
The Hopkins-Xijing collaborators believe their findings point to HCMV inhibition as a mechanism underlying the drug's "geroprotective" effect. The results also suggest "potential repurposing of metformin as a safe and effective treatment for HCMV infection." The investigators hope to do longitudinal studies of metformin on CMV-related immune parameters and disease outcomes.
References
1. Cabreiro F, Au C, Leung KY, et al. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell. 2013;153:228-239.
2. Martin-Montalvo A, Mercken EM, Mitchell SJ, et al. Metformin improves healthspan and lifespan in mice. Nat Commun. 2013;4:2192.
3. Leng S, Ning X, Li Huifen, et al. Metformin suppresses human cytomegalovirus infection: an underlying mechanism for metformin's "geroprotective" effect? 8th International Workshop on HIV and Aging. October 2-3, 2017. New York. Abstract 4.
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