Unknown

Dataset Information

0

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.

SUBMITTER: Taylor HE 

PROVIDER: S-EPMC4447393 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Taylor Harry E HE   Simmons Glenn E GE   Mathews Thomas P TP   Khatua Atanu K AK   Popik Waldemar W   Lindsley Craig W CW   D'Aquila Richard T RT   Brown H Alex HA  

PLoS pathogens 20150528 5


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 permiss  ...[more]

Similar Datasets

| S-EPMC4282136 | biostudies-literature
| S-EPMC3328354 | biostudies-literature
| S-EPMC3698640 | biostudies-other
| S-EPMC3148172 | biostudies-other
| S-EPMC4667845 | biostudies-literature
| S-EPMC7555624 | biostudies-literature
| S-EPMC58783 | biostudies-literature
| S-EPMC3557943 | biostudies-literature
| S-EPMC6778193 | biostudies-literature
| S-EPMC4942332 | biostudies-literature