Fig. 8.

Proposed model of metformin-mediated decrease in HIV transcription in ART-treated PLWH. Shown is the graphical representation of the current knowledge on the effect of metformin on mTOR activation via two mechanisms: 1) an AMP-Activated Protein Kinase (AMPK)-dependent manner by inhibiting mitochondria function and increasing the adenosine monophosphate (AMP):adenosine triphosphate (ATP) ratio, thus leading to AMP-dependent AMPK activation and AMPK-mediated mTORC1 inhibition and 2) an AMPK-independent mechanism via the inhibition of Rag GTPase (RAG) activity, which activates mTORC1 [55], [56], [57]. Subsequently, mTOR pathway activation, as a consequence of its phosphorylation (P), facilitates HIV transcription via the regulation of multiple factors including CDK9 phosphorylation (P), a component of the p-TEFb complex [9], involved in Tat-mediated HIV transcription [49]. Together, our results, reveal the capacity of metformin treatment to reduce residual HIV transcription in ART-treated PLWH by reducing mTOR activation/phosphorylation.