title: Critical role for antiapoptotic Bcl-xL and Mcl-1 in human macrophage survival and cellular IAP1/2 (cIAP1/2) in resistance to HIV-Vpr-induced apoptosis.
abstract: Macrophages are resistant to HIV cytopathic effects, which contributes to viral persistence and reservoir formation. HIV viral protein R (Vpr) is a potent apoptosis-inducing agent for primary monocytes. Because the biologically active Vpr is found in serum and cerebrospinal fluid of HIV-infected patients, we investigated the apoptotic effect of Vpr on monocyte-derived macrophages and phorbol 12-myristate 13-acetate-activated THP1 macrophages. Our results show that primary monocytes and THP1 cells develop resistance to Vpr-induced apoptosis following differentiation into macrophages. To determine the effect of Vpr on the expression of antiapoptotic proteins, we show that in contrast to the undifferentiated cells, Vpr did not down-regulate the expression of antiapoptotic inhibitors of apoptosis (IAPs) and Bcl2 family members in macrophages, suggesting their involvement in resistance to Vpr-induced apoptosis. However, knocking down Bcl-xL and Mcl-1 proteins induced spontaneous apoptosis with no impact on susceptibility to Vpr-induced apoptosis. In contrast, down-regulation of cellular IAP1 (cIAP1) and cIAP2 by using siRNAs and SMAC (second mitochondria-derived activator of caspases) mimetic sensitized macrophages to Vpr-induced apoptosis. Overall, our results suggest that resistance to Vpr-induced apoptosis is specifically mediated by cIAP1/2 genes independent of Bcl-xL and Mcl-1, which play a key role in maintaining cell viability. Moreover, IAP modulation may be a potential strategy to eliminate HIV persistence in macrophages.
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Research Institute, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario K1H 8L1, Canada.
authors.forename: Aurelia
authors.initials: A
authors.lastname: Busca
authors.forename: Mansi
authors.initials: M
authors.lastname: Saxena
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
mesh_terms: D017209:Apoptosis; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D002273:Carcinogens / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D015658:HIV Infections / Q000378:metabolism* / Q000473:pathology; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D008297:Male; D009000:Monocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases; D051020:bcl-X Protein / Q000378:metabolism*; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: C494811:BCL2L1 protein, human; D002273:Carcinogens; D051034:Inhibitor of Apoptosis Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D054325:vpr Gene Products, Human Immunodeficiency Virus; C514912:vpr protein, Human immunodeficiency virus 1; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; D013755:Tetradecanoylphorbol Acetate