title: Phospholipase D1 Couples CD4+ T Cell Activation to c-Myc-Dependent Deoxyribonucleotide Pool Expansion and HIV-1 Replication.
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.
authors.affiliation: Northwestern HIV Translational Research Center, Division of Infectious Diseases, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Harry E
authors.initials: HE
authors.lastname: Taylor
authors.affiliation: Department of Molecular Genetics, University of Texas, Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Glenn E
authors.initials: GE
authors.lastname: Simmons
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Mathews
authors.affiliation: Meharry Medical College, Center for AIDS Health Disparities Research, Nashville, Tennessee, United States of America.
authors.forename: Atanu K
authors.initials: AK
authors.lastname: Khatua
authors.affiliation: Meharry Medical College, Center for AIDS Health Disparities Research, Nashville, Tennessee, United States of America.
authors.forename: Waldemar
authors.initials: W
authors.lastname: Popik
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee, United States of America; Department of Chemistry, Vanderbilt University, Nashville, Tennesee, United States of America; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.affiliation: Northwestern HIV Translational Research Center, Division of Infectious Diseases, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Richard T
authors.initials: RT
authors.lastname: D'Aquila
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee, United States of America; Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: H Alex
authors.initials: HA
authors.lastname: Brown
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004261:DNA Replication; D003854:Deoxyribonucleotides / Q000378:metabolism*; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008213:Lymphocyte Activation; D010739:Phospholipase D / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014779:Virus Replication
chemical_list: D003854:Deoxyribonucleotides; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D010739:Phospholipase D; C106801:phospholipase D1