Abstract
BackgroundTumor necrosis factor-related apoptosis-inducing ligand (TRAIL) could induce apoptosis of HIV-1-infected monocyte-derived macrophage (MDM), but the molecular mechanisms are not well understood.Methodology/Principal FindingsBy using an HIV-1 Env-pseudotyped virus (HIV-1 PV)-infected MDM cell model we demonstrate that HIV-1 PV infection down-regulates the expression of TRAIL decoy receptor 1 (DcR1) and 2 (DcR2), and cellular FLICE-inhibitory protein (c-FLIP), but dose not affect the expression of death receptor 4 and 5 (DR4, DR5), and Bcl-2 family members in MDM cells. Furthermore, recombinant soluble TRAIL and an agonistic anti-DR5 antibody, AD5-10, treatment stimulates reactive oxygen species (ROS) generation and JNK phosphorylation.Conclusions/SignificanceHIV infection facilitates TRIAL-induced cell death in MDM by down-regulating the expression of TRAIL decoy receptors and intracellular c-FLIP. Meanwhile, the agonistic anti-DR5 antibody, AD5-10, induces apoptosis synergistically with TRAIL in HIV-1-infected cells. ROS generation and JNK phosphorylation are involved in this process. These findings potentiate clinical usage of the combination of TRAIL and AD5-10 in eradication of HIV-infected macrophage and AIDS.
Highlights
HIV infection of macrophages is a critically important component of viral pathogenesis and progression to AIDS
The efficacy assay of HIV-1 PV infection by inverted fluorescence microscopy with FITC-labeled anti-HIV-1 p24 antibody demonstrated that more than 90% monocyte-derived macrophage (MDM) cells were infected by the virus, but not the mock-infected control (Fig. 1A), indicating that uniform infection of the MDM cells by HIV-1 PV implemented
This result is consistent with previous report by Tsang et al that MDM cells could well be infected by R5 tropic HIV-1 virus [29]
Summary
HIV infection of macrophages is a critically important component of viral pathogenesis and progression to AIDS. Macrophage contributes an important cellular target for R5tropic strains of HIV-1 and could disseminates the virus to diverse tissues and organs [1]. HIV-1-infected macrophage is considered as the source of viral proteins and of many inflammatory cytokines, which lead to recruitment of additional susceptible T cells to the primary infection site and contribute to that more cells are infected [1,2]. Macrophage dysfunction as well as induction of immune response is responsible for HIV-associated disorder and AIDS development [3,4,5,6]. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) could induce apoptosis of HIV-1-infected monocyte-derived macrophage (MDM), but the molecular mechanisms are not well understood
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