Metformin Treatment Leads to Increased HIV Transcription and Gene Expression through Increased CREB Phosphorylation and Recruitment to the HIV LTR Promoter

Abstract

Antiretroviral therapy has effectively suppressed HIV infection and replication and prolonged the lifespan of HIV-infected individuals. In the meantime, various complications including type 2 diabetes associated with the long-term antiviral therapy have shown steady increases. Metformin has been the front-line anti-hyperglycemic drug of choice and the most widely prescribed medication for the treatment of type 2 diabetes. However, little is known about the effects of Metformin on HIV infection and replication. In this study, we showed that Metformin treatment enhanced HIV gene expression and transcription in HIV-transfected 293T and HIV-infected Jurkat and human PBMC. Moreover, we demonstrated that Metformin treatment resulted in increased CREB expression and phosphorylation, and TBP expression. Furthermore, we showed that Metformin treatment increased the recruitment of phosphorylated CREB and TBP to the HIV LTR promoter. Lastly, we showed that inhibition of CREB phosphorylation/activation significantly abrogated Metformin-enhanced HIV gene expression. Taken together, these results demonstrated that Metformin treatment increased HIV transcription, gene expression, and production through increased CREB phosphorylation and recruitment to the HIV LTR promoter. These findings may help design the clinical management plan and HIV cure strategy of using Metformin to treat type 2 diabetes, a comorbidity with an increasing prevalence, in people living with HIV.

Oxidative phosphorylation in HIV-1 infection: impacts on cellular metabolism and immune function

“…and Guo et al. ( 106 , 111 ). There is an additive effect of risk of metformin-associated lactic acidosis when used with NRTIs like tenofovir, which calls for caution in its clinical application ( 112 , 113 ).…”

“…Therapeutic interventions targeting mitochondrial dysfunction and oxidative stress in HIV immunopathogenesis are emerging as a crucial field of research. Metformin, a diabetes medication, has shown varying effects on HIV-1 replication in studies by Rezai et al and Guo et al (106,111). There is an additive effect of risk of metformin-associated lactic acidosis when used with NRTIs like tenofovir, which calls for caution in its clinical application (112,113).…”