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

The EMBO Journal
Petra MlcochovaRavindra K Gupta

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.

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Citations

Mar 28, 2018·Autoimmunity·Christopher H Mauney, Thomas Hollis
Mar 9, 2018·Scientific Reports·Paula Jáuregui, Nathaniel R Landau
Apr 10, 2020·European Journal of Immunology·Lorena Valverde-EstrellaAntonio Celada
Apr 5, 2020·Viruses·Si'Ana A CogginsBaek Kim
Aug 6, 2020·Viruses·Isabella A T M FerreiraPetra Mlcochova
Dec 24, 2018·Frontiers in Immunology·Marta Colomer-LluchJulia G Prado
Apr 4, 2018·Biochemical and Biophysical Research Communications·Ana Carla MedeirosMarcelo D Gomes
May 25, 2021·Frontiers in Cellular and Infection Microbiology·J Peter Svensson
Oct 26, 2021·Journal of Molecular Biology·Andrew LopezOliver I Fregoso

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Methods Mentioned

BETA
nuclear translocation
FACS
FCS
transfection
flow cytometry
PCR

Software Mentioned

ImageJ
MetaMorph
AlphaView
FlowJo

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