Phospholipase D1 Couples CD4+ T Cell Activation to c-Myc-Dependent Deoxyribonucleotide Pool Expansion and HIV-1 Replication

Harry E. Taylor*, Glenn E. Simmons, Thomas P. Mathews, Atanu K. Khatua, Waldemar Popik, Craig W. Lindsley, Richard T. D’Aquila, H. Alex Brown

*Corresponding author for this work

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Quiescent CD4+ T cells restrict human immunodeficiency virus type 1 (HIV-1) infection at early steps of virus replication. Low levels of both deoxyribonucleotide triphosphates (dNTPs) and the biosynthetic enzymes required for their de novo synthesis provide one barrier to infection. CD4+ T cell activation induces metabolic reprogramming that reverses this block and facilitates HIV-1 replication. Here, we show that phospholipase D1 (PLD1) links T cell activation signals to increased HIV-1 permissivity by triggering a c-Myc-dependent transcriptional program that coordinates glucose uptake and nucleotide biosynthesis. Decreasing PLD1 activity pharmacologically or by RNA interference diminished c-Myc-dependent expression during T cell activation at the RNA and protein levels. PLD1 inhibition of HIV-1 infection was partially rescued by adding exogenous deoxyribonucleosides that bypass the need for de novo dNTP synthesis. Moreover, the data indicate that low dNTP levels that impact HIV-1 restriction involve decreased synthesis, and not only increased catabolism of these nucleotides. These findings uncover a unique mechanism of action for PLD1 inhibitors and support their further development as part of a therapeutic combination for HIV-1 and other viral infections dependent on host nucleotide biosynthesis.

Original languageEnglish (US)
Article numbere1004864
JournalPLoS pathogens
Volume11
Issue number5
DOIs
StatePublished - May 1 2015

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

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    Taylor, H. E., Simmons, G. E., Mathews, T. P., Khatua, A. K., Popik, W., Lindsley, C. W., D’Aquila, R. T., & Brown, H. A. (2015). Phospholipase D1 Couples CD4+ T Cell Activation to c-Myc-Dependent Deoxyribonucleotide Pool Expansion and HIV-1 Replication. PLoS pathogens, 11(5), [e1004864]. https://doi.org/10.1371/journal.ppat.1004864