c-Myc Links TGF-β Signaling to Metabolic Control of HIV Reactivation in OM10.1 Cells

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Abstract
Antiretroviral therapy (ART) suppresses HIV replication but does not eliminate persistent viral reservoirs, which can rapidly reseed viremia following treatment interruption. We previously showed that blockade of transforming growth factor beta (TGF-β) signaling in vivo promotes SIV latency reversal and is associated with reversal of cellular metabolic quiescence. Here, using the provirally infected promyelocytic OM10.1 cell line, we investigated the cell-intrinsic mechanisms through which TGF-β regulates HIV reactivation. TGF-β inhibited proviral reactivation following stimulation with distinct latency-reversing agents, and this effect was reversed by pharmacologic inhibition of TGF-β signaling. TGF-β reduced HIV transcription without suppressing TNF-α-induced NF-κB activation, suggesting inhibition through an alternative mechanism. Bulk RNA sequencing revealed broad suppression of c-Myc-associated pathways, oxidative phosphorylation, and mTORC1 signaling. Functional metabolic profiling confirmed marked reductions in both glycolytic and mitochondrial ATP production and decreased mitochondrial membrane polarization. Consistent with a functional link between metabolism and viral reactivation, mitochondrial uncoupling strongly inhibited HIV expression. Finally, MYC overexpression completely rescued HIV transcription and partially restored p24 production in TGF-β-treated cells. Together, these findings identify a cell-intrinsic mechanism through which TGF-β restrains HIV reactivation by imposing a metabolically quiescent state, mediated at least in part through suppression of c-Myc.
Funding Information
  • National Institutes of Health (R01 AI176599)
  • Third Coast CFAR (P30 Al117943)

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