Cell Cycle Control and HIV-1 Susceptibility Are Linked by CDK6-Dependent CDK2 Phosphorylation of SAMHD1 in Myeloid and Lymphoid Cells


Eduardo Pauls et al. J Immunol. 2014 Jul 11. pii: 1400873


Proliferating cells are preferentially susceptible to infection by retroviruses. Sterile α motif and HD domain-containing protein-1 (SAMHD1) is a recently described deoxynucleotide phosphohydrolase controlling the size of the intracellular deoxynucleotide triphosphate (dNTP) pool, a limiting factor for retroviral reverse transcription in noncycling cells. Proliferating (Ki67+) primary CD4+ T cells or macrophages express a phosphorylated form of SAMHD1 that corresponds with susceptibility to infection in cell culture. We identified cyclin-dependent kinase (CDK) 6 as an upstream regulator of CDK2 controlling SAMHD1 phosphorylation in primary T cells and macrophages susceptible to infection by HIV-1. In turn, CDK2 was strongly linked to cell cycle progression and coordinated SAMHD1 phosphorylation and inactivation. CDK inhibitors specifically blocked HIV-1 infection at the reverse transcription step in a SAMHD1-dependent manner, reducing the intracellular dNTP pool. Our findings identify a direct relationship between control of the cell cycle by CDK6 and SAMHD1 activity, which is important for replication of lentiviruses, as well as other viruses whose replication may be regulated by intracellular dNTP availability.


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Eduardo Pauls, Alba Ruiz, Roger Badia, Marc Permanyer, Albert Gubern, Eva Riveira-Muñoz, Javier Torres-Torronteras, Mar Álvarez, Beatriz Mothe, Christian Brander, Manel Crespo‖, Luis Menéndez-Arias, Bonaventura Clotet, Oliver T. Keppler, Ramon Martí, Francesc Posas, Ester Ballana and José A. Esté


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Grupos de IrsiCaixa vinculados: Inmunidad Celular y Genética del huéspedPatogénesis del VIH