Fig. 7

PIM kinase inhibitors block lentiviral replication in primary macrophages. a, b HIV-2 replication kinetics in primary monocyte–derived macrophages. Schematic representation of the experimental design (a). Cells were infected with wild-type HIV-2_GL-AN or HIV-1_89.6 in the presence of AZD1208 or SGI1776 (1 µM). A HIV protease inhibitor darunavir (DRV, 1 µM) was used as a control. Replication kinetics were monitored by ELISA of extracellular viral p27 or p24 capsid antigens (b). c, d PIM kinase inhibitors can block SIV replication ex vivo. Schematic representation of the experimental procedure (c). Cells derived from a lymph node of an SIV-infected macaque monkey were seeded onto dishes. After suspension cells were removed, the remaining cells were stimulated with TNF-α (50 ng ml⁻¹) for 24 h, and then treated with either AZD1208, SGI1776, or DRV (1 µM) for 7 days. The levels of progeny virions in culture supernatants were determined by SIV p27 ELISA (d). e Schematic diagram illustrating the proposed role of PIM kinases in lentiviral infection. In infected macrophages, Vpx targets SAMHD1 for ubiquitination and proteasomal degradation by forming CRL4 E3 ubiquitin ligase complex. PIM family kinases (PIM1 and PIM3) target a highly conserved residue of Vpx, Ser13, and that this phosphorylation stabilizes the binding of Vpx to SAMHD1, resulting in efficient SAMHD1 degradation and viral replication. All graphs are presented as a mean ± s.d. (n = 3). *P < 0.05; **P < 0.01, two-tailed unpaired t-test. Source data are provided as a Source Data file