mTOR Overcomes Multiple Metabolic Restrictions to Enable HIV-1 Reverse Transcription and Intracellular Transport

Harry E. Taylor*, Nina Calantone, Drew Lichon, Hannah Hudson, Isabelle Clerc, Edward M. Campbell, Richard T. D'Aquila

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Cellular metabolism governs the susceptibility of CD4 T cells to HIV-1 infection. Multiple early post-fusion steps of HIV-1 replication are restricted in resting peripheral blood CD4 T cells; however, molecular mechanisms that underlie metabolic control of these steps remain undefined. Here, we show that mTOR activity following T cell stimulatory signals overcomes metabolic restrictions in these cells by enabling the expansion of dNTPs to fuel HIV-1 reverse transcription (RT), as well as increasing acetyl-CoA to stabilize microtubules that transport RT products. We find that catalytic mTOR inhibition diminishes the expansion of pools of both of these metabolites by limiting glucose and glutamine utilization in several pathways, thereby suppressing HIV-1 infection. We demonstrate how mTOR-coordinated biosyntheses enable the early steps of HIV-1 replication, add metabolic mechanisms by which mTOR inhibitors block HIV-1, and identify some metabolic modules downstream of mTOR as druggable targets for HIV-1 inhibition.

Original languageEnglish (US)
Article number107810
JournalCell reports
Volume31
Issue number12
DOIs
StatePublished - Jun 23 2020

Keywords

  • CD4 T cells
  • HIV-1
  • HIV-1 replication
  • host-virus interactions
  • immunometabolism
  • mTOR
  • mTORC1
  • mTORC2
  • microtubule stabilization
  • reverse transcription

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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