Palbociclib, a selective inhibitor of cyclin-dependent kinase4/6, blocks HIV-1 reverse transcription through the control of sterile α motif and HD domain-containing protein-1 (SAMHD1) activity

被引:40
作者
Pauls, Eduardo [1 ,2 ]
Badia, Roger [1 ,2 ]
Torres-Torronteras, Javier [3 ,4 ]
Ruiz, Alba [1 ,2 ]
Permanyer, Marc [1 ,2 ]
Riveira-Munoz, Eva [1 ,2 ]
Clotet, Bonaventura [1 ,2 ]
Marti, Ramon [3 ,4 ]
Ballana, Ester [1 ,2 ]
Este, Jose A. [1 ,2 ]
机构
[1] Univ Autonoma Barcelona, Hosp Germans Trias & Pujol, AIDS Res Inst IrsiCaixa, Badalona, Spain
[2] Univ Autonoma Barcelona, Hosp Germans Trias & Pujol, AIDS Unit, Badalona, Spain
[3] Univ Autonoma Barcelona, Vall dHebron Inst Recerca, Res Grp Neuromuscular & Mitochondrial Disorders, Valencia, Spain
[4] Inst Salud Carlos III, Biomed Network Res Ctr Rare Dis CIBERER, Valencia, Spain
关键词
CDK2; CDK6; HIV-1; restriction factor; SAMHD1; IMMUNODEFICIENCY-VIRUS TYPE-1; DEOXYNUCLEOSIDE TRIPHOSPHATE TRIPHOSPHOHYDROLASE; RESTRICTION FACTOR SAMHD1; CD4(+) T-CELLS; PRIMARY MACROPHAGES; REPLICATION; PROGRESSION; INFECTION; PHASE; PHOSPHORYLATION;
D O I
10.1097/QAD.0000000000000399
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Background:Sterile motif and HD domain-containing protein-1 (SAMHD1) inhibits HIV-1 reverse transcription by decreasing the pool of intracellular deoxynucleotides. SAMHD1 is controlled by cyclin-dependent kinase (CDK)-mediated phosphorylation. However, the exact mechanism of SAMHD1 regulation in primary cells is unclear. We explore the effect of palbociclib, a CDK6 inhibitor, in HIV-1 replication.Methods:Human primary monocytes were differentiated into macrophages with monocyte-colony stimulating factor and CD4(+) T lymphocytes stimulated with phytohaemagglutinin (PHA)/interleukin-2. Cells were treated with palbociclib and then infected with a Green fluorescent protein-expressing HIV-1 or R5 HIV-1 BaL. Viral DNA was measured by quantitative PCR and infection assessed by flow cytometry. Deoxynucleotide triphosphate (dNTP) content was determined using a polymerase-based method.Results:Pan-CDK inhibitors AT7519, roscovitine and purvalanol A reduced SAMHD1 phosphorylation. HIV-1 replication was blocked by AT7519 (66.43.8%; n=4), roscovitine (47.3 +/- 3.9%; n=4) and purvalanol A (55.7 +/- 15.7%; n=4) at subtoxic concentrations. Palbociclib, a potent and selective CDK6 inhibitor, blocked SAMHD1 phosphorylation, intracellular dNTP levels, HIV-1 reverse transcription and HIV-1 replication in primary macrophages and CD4(+) T lymphocytes. Notably, treatment of macrophages with palbociclib led to reduced CDK2 activation, measured as the phosphorylation of the T-loop at the Thr160. The antiviral effect was lost when SAMHD1 was degraded by Vpx, providing further evidence for a role of SAMHD1 in mediating the antiretroviral effect.Conclusions:Our results indicate that SAMHD1-mediated HIV-1 restriction is controlled by CDK as previously suggested but point to a preferential role for CDK2 and CDK6 as mediators of SAMHD1 activation. Our study provides a new signaling pathway susceptible for the development of new therapeutic approaches against HIV-1 infection.
引用
收藏
页码:2213 / 2222
页数:10
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