Advertisement

 

 

DNA damage induced by topoisomerase inhibitors activates SAMHD1 and blocks HIV-1 infection of macrophages.

DNA damage induced by topoisomerase inhibitors activates SAMHD1 and blocks HIV-1 infection of macrophages.
Author Information (click to view)

Mlcochova P, Caswell SJ, Taylor IA, Towers GJ, Gupta RK,


Mlcochova P, Caswell SJ, Taylor IA, Towers GJ, Gupta RK, (click to view)

Mlcochova P, Caswell SJ, Taylor IA, Towers GJ, Gupta RK,

Advertisement
Share on FacebookTweet about this on TwitterShare on LinkedIn

The EMBO journal 2017 10 3037(1) 50-62 doi 10.15252/embj.201796880
Abstract

We report that DNA damage induced by topoisomerase inhibitors, including etoposide (ETO), results in a potent block to HIV-1 infection in human monocyte-derived macrophages (MDM). SAMHD1 suppresses viral reverse transcription (RT) through depletion of cellular dNTPs but is naturally switched off by phosphorylation in a subpopulation of MDM found in a G1-like state. We report that SAMHD1 was activated by dephosphorylation following ETO treatment, along with loss of expression of MCM2 and CDK1, and reduction in dNTP levels. Suppression of infection occurred after completion of viral DNA synthesis, at the step of 2LTR circle and provirus formation. The ETO-induced block was completely rescued by depletion of SAMHD1 in MDM Concordantly, infection by HIV-2 and SIVsm encoding the SAMHD1 antagonist Vpx was insensitive to ETO treatment. The mechanism of DNA damage-induced blockade of HIV-1 infection involved activation of p53, p21, decrease in CDK1 expression, and SAMHD1 dephosphorylation. Therefore, topoisomerase inhibitors regulate SAMHD1 and HIV permissivity at a post-RT step, revealing a mechanism by which the HIV-1 reservoir may be limited by chemotherapeutic drugs.

Submit a Comment

Your email address will not be published. Required fields are marked *

1 × four =

[ HIDE/SHOW ]