Chronic HIV Type 1 Infection Down-regulates Expression of DAP Kinase and p19 ARF -p53 Checkpoint and Is Associated with Resistance to CD95-Mediated Apoptosis in HUT78 T Cells

Abstract

Death-associated protein kinase (DAP kinase) is a proapoptotic serine/threonine kinase that has been shown to play a role in both death-receptor signaling and mitochondrial signaling pathways of apoptosis. DAP kinase activates the p19^ARF-p53 apoptotic checkpoint. In this study we report that the expression of DAP kinase, p19^ARF, p53, and p21^WAF1 was significantly down-regulated in the chronically HIV-1_SF2-infected HUT78 T cells (HUT78/HIV-1_SF2) as compared to uninfected HUT78 cells. An increased proportion of HUT78/HIV1_SF2 cells was detected in S phase and a decreased proportion in G_o/G₁ phase indicating that more HUT78/HIV1_SF2 cells progressed through the G₁/S transition. Furthermore, HUT78/HIV-1_SF2 cells showed increased resistance to CD95-mediated apoptosis as compared to HIV-1_SF2-uninfected HUT78 cells and activation of caspase-3, -8, and -9 was significantly reduced in HUT78/HIV-1_SF2 cells. These data suggest that down-regulation of DAP kinase and downstream signaling factors may be one of the mechanism that HIV-1 may employ to protect the infected host cells from cell death and to allow persistent HIV-1 replication.