title: TRAIL-mediated apoptosis in HIV-1-infected macrophages is dependent on the inhibition of Akt-1 phosphorylation.
abstract: HIV-1 uses mononuclear phagocytes (monocytes, tissue macrophages, and dendritic cells) as a vehicle for its own dissemination and as a reservoir for continuous viral replication. The mechanism by which the host immune system clears HIV-1-infected macrophages is not understood. TRAIL may play a role in this process. TRAIL is expressed on the cell membrane of peripheral immune cells and can be cleaved into a soluble, secreted form. The plasma level of TRAIL is increased in HIV-1-infected patients, particularly those with high viral loads. To study the effect of elevated TRAIL on mononuclear phagocytes, we used recombinant human (rh) TRAIL and human monocyte-derived macrophages (MDM) as an in vitro model. Our results demonstrated rhTRAIL-induced apoptosis in HIV-1-infected MDM and inhibited viral replication, while having a reduced effect on uninfected MDM. HIV-1 infection significantly decreased Akt-1 phosphorylation; rhTRAIL exposure further decreased Akt-1 phosphorylation. Infection with a dominant-negative Akt-1 adenovirus potentiated rhTRAIL-induced apoptosis, while constitutively active Akt-1 blocked rhTRAIL-induced apoptosis in HIV-1-infected MDM. From this data we conclude the death ligand TRAIL preferentially provokes apoptosis of HIV-1-infected MDM, and the mechanism is reliant upon the inhibition of Akt-1 phosphorylation. Understanding this mechanism may facilitate the elimination of HIV-1-infected macrophages and lead to new therapeutic avenues for treatment of HIV-1 infection.
authors.affiliation: Laboratory of Neurotoxicology, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Huang
authors.forename: Nathan
authors.initials: N
authors.lastname: Erdmann
authors.forename: Hui
authors.initials: H
authors.lastname: Peng
authors.forename: Shelley
authors.initials: S
authors.lastname: Herek
authors.forename: John S
authors.initials: JS
authors.lastname: Davis
authors.forename: Xu
authors.initials: X
authors.lastname: Luo
authors.forename: Tsuneya
authors.initials: T
authors.lastname: Ikezu
authors.forename: Jialin
authors.initials: J
authors.lastname: Zheng
mesh_terms: D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D002478:Cells, Cultured; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000201:enzymology* / Q000821:virology*; D008562:Membrane Glycoproteins / Q000502:physiology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D051057:Proto-Oncogene Proteins c-akt