期刊
EMBO JOURNAL
卷 37, 期 1, 页码 50-62出版社
WILEY
DOI: 10.15252/embj.201796880
关键词
DNA damage; HIV; integration; macrophage; SAMHD1
资金
- Wellcome Trust Senior Fellowship in Clinical Science [WT108082AIA]
- Wellcome Trust Senior Biomedical Research Fellowship [WT108183]
- European Research Council under the European Union's Seventh Framework Programme (FP7)/ERC grant [339223]
- Francis Crick Institute from Cancer Research UK [FC001178]
- UK Medical Research Council [FC001178]
- Wellcome Trust [FC001178]
- Wellcome Trust Senior Investigator Award [108014/Z/15/Z]
- Wellcome Trust [108014/Z/15/Z, 108183/Z/15/Z] Funding Source: Wellcome Trust
- MRC [G9721629, G0801172] Funding Source: UKRI
- Medical Research Council [G0801172, 1195793, G9721629] Funding Source: researchfish
- The Francis Crick Institute [10421, 10178] Funding Source: researchfish
- Wellcome Trust [108183/Z/15/Z] Funding Source: researchfish
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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