title: HIV infection enhances TRAIL-induced cell death in macrophage by down-regulating decoy receptor expression and generation of reactive oxygen species.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  By 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
  HIV 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.
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Dan-Ming
authors.initials: DM
authors.lastname: Zhu
authors.forename: Juan
authors.initials: J
authors.lastname: Shi
authors.forename: Shilian
authors.initials: S
authors.lastname: Liu
authors.forename: Yanxin
authors.initials: Y
authors.lastname: Liu
authors.forename: Dexian
authors.initials: D
authors.lastname: Zheng
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D004357:Drug Synergism; D057809:HEK293 Cells; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D009000:Monocytes / Q000166:cytology; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000737:chemistry / Q000494:pharmacology*; D053319:Tumor Necrosis Factor Decoy Receptors / Q000276:immunology / Q000378:metabolism*; D017735:Virus Latency / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D053319:Tumor Necrosis Factor Decoy Receptors; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases