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

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. © 2015 taylor et al.